sexta-feira, 31 de dezembro de 2010

Lula disse não e extradição



Caso Battisti, difícil decisão, mas ficar em prisão no Brasil deve muito pior que a extradição. Ver Berlusconi contrariado não tem preço.








Battisti, Lula dice no all'estradizione
Il presidente brasiliano nega il rimpatrio dell'ex terrorista. Critiche al governo: «Italia impertinente»


Cesare Battisti al momento del suo arresto in Brasile nel marzo 2007 (Ansa)MILANO - Cesare Battisti non sarà estradato in Italia. Il presidente Brasiliano, Ignacio Lula da Silva, ha deciso di seguire l'orientamento già espresso dall'Avvocatura generale dello Stato che giovedì si era detta contraria al rinvio in Italia dell'ex terrorista dei Pac, i Proletari armati per il comunismo, accusato di quattro omicidi per i quali non aveva mai scontato alcuna pena. Il presidente del Consiglio, Silvio Berlusconi, ha commentato negativamente la decisione di Lula e ha fatto sapere che «la vicenda è tutt'altro che chiusa», annunciando che l'Italia farà tutto il possibile per far valere i propri diritti. Il ministro degli Esteri, Franco Frattini, ha intanto richiamato l'ambasciatore italiano a Brasilia per comunicazioni. Vissuto per anni da latitante a Parigi, Battisti era poi fuggito prima dell'estradizione che l'Eliseo sembrava intenzionato a concedere e si era rifugiato in Brasile, dove era stato poi fermato nel marzo 2007. Sostenuto da un movimento di opinione contrario all'estradizione, Battisti ha sperato fino all'ultimo nel diniego del capo dello stato al suo trasferimento in Italia. E la sua speranza è stata ripagata. Lula ha preso la sua decisione nell'ultimo giorno di permanenza alla guida del Paese, prima di passare la mano a Dilma Rousseff, vincitrice delle ultime presidenziali, che a giugno, interpellata in proposito, si era detta favorevole all'estradizione: «Si dovrà applicare la decisione del Supremo Tribanle Federale» aveva detto.

«ITALIA IMPERTINENTE» - La decisione di Lula è stata annunciata dal ministro brasiliano degli Esteri, Celso Amorim che ha anche fatto sapere che il governo brasiliano considera «impertinente in particolare nel riferimento personale a Lula» la nota diffusa ieri dal governo italiano circa il caso Battisti, laddove si definiva «incomprensibile e inaccettabile» un eventuale no all'estradizione. Secondo la nota del governo di Brasilia, la decisione di Lula non rappresenta un affronto verso un altro Paese «nel momento in cui si creano situazioni particolari che possono generare rischi per la persona, nonostante il carattere democratico dei due Stati». Il ministro Amorim ha detto di non ritenere che il presidente Lula si metterà in contatto con le autorità italiane. Lo stesso esponente del governo brasiliano ha detto di non credere che la decisione di oggi possa pregiudicare i rapporti tra i due Stati.

TORREGIANI: VERGOGNA - Alberto Torregiani, figlio del gioielliere ucciso nel 1979, a sua volta colpito dai proiettili sparati terroristi e da allora costretto a muoversi su una sedia a rotelle, appena appresa la notizia, ha definito la decisione di Lula «una vergogna incomprensibile» e ha indicato il boicottaggio del Brasile come unica soluzione. Al di lá dell'indignazione, il figlio di Torregiani crede sia giunta l'ora di passare ai «fatti concreti». Ecco perchè il prossimo 4 gennaio, davanti all'ambasciata brasiliana a Roma si terrà un sit in. «L'Italia tutta unita - ha detto - deve scendere in piazza. Estendo la partecipazione anche ai politici, di destra e di sinistra. Non vogliamo bandiere perchè nella nostra manifestazione non si devono creare distinguo politici». In quell'occasione, sará ufficializzata la nascita del Comitato vittime di Battisti. «Un comitato - ha precisato Torregiani - apartitico e apolitico. Deve essere ben chiaro che questo non è solo un problema italiano». Torregiani ha detto di vivere la decisione del governo brasiliano come una «colossale presa per i fondelli». «Abbiamo sempre agito in maniera pacata, nel rispetto delle regole e ora ci troviamo davanti ad una decisione assurda e incomprensibile - ha detto - . Sarebbe stato più nobile dirlo subito e invece hanno giocato con le nostre vite, con i nostri sentimenti. La misura è colma».

L'AVVOCATO: «FELICE» - «Sono felice»: è il commento del legale di Cesare Battisti, Luis Roberto Barroso, al no del governo Lula all'estradizione dell'ex terrorista in Italia. In una nota, l'avvocato ha sottolineato che con questa decisione il Brasile ha confermato la propria «tradizione umanitaria» e respinto d'altro lato «le pressioni fatte con tono inappropriato dal governo italiano». Ribadendo quanto già detto più volte negli ultimi mesi, Barroso ha definito «innocente» Battisti, contro il quale - ha precisato - «i veri colpevoli» degli omicidi dei quali è stato accusato «hanno trasferito» tali responsabilità. «Si tratta - ha concluso - di pentiti o di delatori che sono stati premiati».

CASO ANCORA APERTO - Il caso, tuttavia, non è affatto chiuso. Anzi è destinato ad andare avanti anche nelle prossime settimane secondo quanto scriveva oggi la stampa brasiliana, nell'attesa del «verdetto» del presidente. Veniva in particolare rilevato come Battisti dovrà comunque rimanere in carcere fino a febbraio. Il «dossier Battisti» dovrà infatti tornare, per una nuova analisi del caso, nel Supremo Tribunal Federal (Stf) del Brasile. Tale nuova valutazione potrà avvenire solo a febbraio, quando l'Stf riprenderà le attività dopo la pausa estiva in Brasile, ha detto Peluso alla Folha de São Paulo, secondo la quale il relatore del caso nella nuova analisi dell'Alta Corte sarà Gilmar Mendes, ex presidente dell'Stf che un anno fa, quando il caso Battisti venne esaminato dal tribunale, votò a favore dell'estradizione.

LE REAZIONI IN ITALIA - In Italia la vicenda continua a tenere vivo il dibattito politico. Diversi esponenti del governo, da Bossi a Calderoli, da Giorgia Meloni a Ignazio La Russa, avevano ipotizzato ritorsioni più o meno eclatanti in caso di pronunciamento contrario all'estradizione. Anche diversi esponenti del Pd e dell'Idv si sono detti favorevoli all'estradizione e solo il segretario di Rifondazione comunista, Paolo Ferrero, aveva detto di considerare eccessive le reazioni invitando tutti ad accettare con serenità le decisioni del presidente Lula, qualunque fosse stato l'orientamento emerso.

Le Monde comenta a posse de Dilma Roussef

















Un ouvrier, une femme. Pour la deuxième fois, la démocratie brésilienne, naguère violentée, aujourd'hui vibrante, innove avec bonheur. Samedi 1erjanvier, l'ancien "métallo" Luiz Inacio Lula da Silva cédera son fauteuil à sa dauphine, Dilma Rousseff, l'ex-guérillera, devenue économiste et technocrate, élue il y a deux mois première femme présidente du Brésil.

"Dilma", comme chacun l'appelle, accède à la fonction suprême dans un contexte bien plus enviable que celui de 2002. Nul besoin, comme alors, de rassurer les milieux d'affaires qu'effrayait encore, malgré ses promesses apaisantes, le syndicaliste barbu. Grâce au pragmatisme de Lula, jamais démenti en huit ans, les capitaux affluent désormais à la Bourse de SaoPaulo, pour s'investir ou spéculer.

La nouvelle présidente bénéficie de l'héritage de son prédécesseur. Une démocratie consolidée, délivrée de l'inflation, à la richesse décuplée par l'envol du cours des matières premières. Croissance, emploi, consommation, monnaie : les grands indicateurs du Brésil sont au vert. Avec, en prime, un fabuleux trésor pétrolier qui dort au large de ses côtes.

Au réalisme économique s'ajoute une relative audace sociale. Grâce au dynamisme ambiant et à une gamme d'aides familiales, quinze millions de Brésiliens ont, depuis huit ans, échappé au chômage, intégré l'économie formelle et cessé d'être pauvres ou très pauvres. Ils ont rejoint l'armée grandissante des classes moyennes, avides de posséder, de consommer et de mieux vivre.

Comme toute entreprise inachevée, celle de Lula comporte sa part d'ombre, où Dilma Rousseff affrontera ses plus grands défis. L'enseignement reste médiocre et inégalitaire. Le système de santé fonctionne à deux vitesses. La violence et l'insécurité gangrènent les métropoles. La corruption et le népotisme rongent la vie publique dans un pays où la politique est souvent perçue comme un simple moyen de s'enrichir. Les infrastructures exigent d'être rapidement développées pour relever notamment le défi du Mondial de football (2014) et des Jeux olympiques (2016).

Lula lègue à la nouvelle présidente un pays écouté et respecté dans l'arène internationale. Le Brésil y est devenu un acteur majeur qui s'attire beaucoup de louanges et déjà quelques reproches, par exemple à propos de son rapprochement avec le régime de Téhéran. Dans ce domaine, "Dilma" a commencé à faire entendre sa différence en exprimant avec force son souci des droits humains, en particulier ceux des femmes, en Iran et ailleurs.

Mme Rousseff doit son glorieux destin au soutien inflexible de son mentor, dont elle ne possède ni le charisme ni les dons de tribun, il est vrai hors de pair. Elle aura sans doute à coeur de s'émanciper peu à peu de cette tutelle bienveillante. Professeur d'optimisme, Lula a dopé le moral de la nation. Cette confiance collective profite à sa protégée. Plus de quatre Brésiliens sur cinq prédisent qu'elle gouvernera aussi bien, voire mieux, que le président le plus populaire de l'histoire du Brésil. A elle de ne pas les décevoir.

TRADUÇAO

Um trabalhador, uma mulher. Pela segunda vez, a democracia brasileira, uma vez violentada, hoje vibrante, inova com a felicidade. Sábado 1 de janeiro, o antigo "metalurgico" Luiz Inácio Lula da Silva vai render seu assento a seu sucessor, Dilma Rousseff, ex-guerrilheira, tornou-se uma economista e tecnocrata, eleita há dois meses, será a primeira mulher presidente do Brasil.


"Dilma," como todos o chamam, ocupará o cargo mais alto em muito mais invejável que a de 2002. Não há necessidade, como foi que para tranqüilizar a comunidade empresarial assustada, apesar das promessas do sindicalista barbudo. Graças ao pragmatismo de Lula, infalível em oito anos, o capital está fluindo agora em São Paulo Stock Exchange, para investir ou especular.

O novo presidente conta com o legado de seu antecessor. Uma democracia consolidada, livre da inflação, a riqueza aumentada pelo aumento dos preços das commodities (soja,petroleo,carne etc). Crescimento, emprego, consumo, moeda: os principais indicadores do Brasil é verde. Com a vantagem adicional de um fabuloso tesouro que dorme de petróleo ao largo da costa.

Além disso, o realismo econômico ousadia relação social. Graças a uma dinâmica envolvente e uma série de tarefas domésticas, quinze milhões de brasileiros escapou do desemprego, integrados na economia formal deixaram de ser pobres ou muito pobres. Eles se juntaram ao exército crescente de classes médias, ávidos de possuir, consumir e viver melhor.

Como em qualquer negócio inacabado, Lula deixou seu lado escuro, onde Dilma Rousseff vai enfrentar seus maiores desafios. Educação continua pobre e desigual. O sistema de saúde funciona ainda precario. Violência e insegurança nas metrópoles. Corrupção e nepotismo na vida pública corroer um país onde a política é muitas vezes visto apenas como um meio de se enriquecer. Infra-estrutura necessária precisa ser desenvolvida rapidamente para enfrentar o desafio especial da Copa do Mundo (2014) e olímpico (2016).

Lula deixa para novo presidente do país que é ouvido e respeitado na arena internacional. Brasil está se tornando um grande país que recebe um monte de elogios e algumas críticas já, por exemplo, sobre sua aproximação com o regime de Teerã. Neste domínio, "Dilma" começará a ser ouvida e expressar suas diferenças com a força de sua preocupação com os direitos humanos, especialmente os das mulheres.

Dilma deve o seu destino glorioso inabalável apoio de seu mentor, que ela não tem nem o carisma nem os dons da tribuna, de fato inigualável. Ela, sem dúvida, esta disposta a libertar-se gradualmente desta tutela benevolente.

Professor de otimismo, Lula impulsionou a moral da nação. Essa confiança coletiva beneficia sua protegida. Mais do que quatro em cada cinco brasileiros prevêem que ela irá governar tão bem ou melhor do que, o presidente mais popular da história do Brasil.

Ela não irá decepcioná-los

quinta-feira, 30 de dezembro de 2010

a regulação do FOXP3 depende de FOXO Immunity


Foxo1 and Foxo3 help Foxp3
Naganari Ohkura1, 2, , and Shimon Sakaguchi1, 2
1 Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
2 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan

In this issue of Immunity, Kerdiles et al. (2010) report that Foxo transcription factors are essential for the development and function of Foxp3-expressing regulatory T (Treg) cells via controlling the expression of genes associated with Treg cell function.
Foxo transcription factors belong to the Forkhead box family of transcription factors characterized by a conserved winged helix DNA binding domain. In mammals, the Foxo subfamily is comprised of four members, Foxo1, Foxo3, Foxo4, and Foxo6. Foxo1 and Foxo3 are the main isoforms expressed in the immune system. They are important regulators of cell cycle progression, apoptosis, glucose metabolism, and stress resistance via integrating information of the presence of nutrients, growth factors, and stress signals. Recent studies have shown that Foxo transcription factors are also associated with lymphocyte functions such as gene recombination, homing, and cytokine receptor expression. Although Foxo transcription factors appear to play important roles in a variety of biological processes, the functions of Foxo1 and Foxo3 in T cells still remain obscure. In this issue of Immunity, Kerdiles et al. (2010) investigate autoimmunity resulting from T cell-specific deletion of Foxo1 and additional deletion of Foxo3. They conclude that Foxo transcription factors are essential for specifying the program of T cell differentiation especially into regulatory T (Treg) cells expressing the transcription factor Foxp3 (Figure 1).


Full-size image (42K)
High-quality image (262K)

<>Figure 1.
Foxo1 and Foxo3 Are Necessary for the Development and Function of Regulatory T cells
The PI3K-Akt pathway is an upstream signal for the Foxo family members. It induces phosphorylation of Foxo transcriptional factors and their nuclear export into the cytoplasm. Foxo1 and Foxo3 bind to the promoter regions of Foxp3 and CTLA-4 and other genes. Those factors are required for the adequate gene expression of Foxp3 and its target genes, such as CTLA-4, in Treg cells.

Foxo transcription factors can act as either transcriptional activators or repressors by forming different molecular complexes with different transcriptional modulators including β-catenin, STAT3, Runx3, Smad3, or Smad4. In addition, their function is tightly regulated by the upstream phosphoinositide 3-kinase (PI3K) and Akt pathway, which phosphorylates Foxo molecules and facilitates their nuclear export into the cytoplasm. After antigen or cytokine stimulation, Foxo transcription factors are rapidly phosphorylated and deactivated in a PI3K-dependent manner, whereas cytokine withdrawal elicits their dephosphorylation and activation. Foxo transcription factors are therefore the major downstream target of the PI3K-Akt signaling pathway. In immune cells, the PI3K pathway is activated by several stimuli via specific receptors, including the B cell antigen receptor (BCR), T cell antigen receptor (TCR), and cytokine and chemokine receptors. Thus Foxos may well play an essential part in immune cell functions.
Kerdiles et al. (2010) made mice with a T cell-specific deletion of Foxo1 by crossing Cd4-cre mice with Foxo1f/f mice. They found that mice with a T cell-specific deletion of Foxo1 harbor an expanded population of activated and/or memory CD4+CD44hi T cells and developed B cell autoimmunity as evidenced by B cell activation, hypergammaglobulinemia, and the production of autoantibodies. Young mice with conditional deletion of Foxo1 in CD4+ T cells exhibited a noticeable decrease in the proportion and the number of Foxp3+ Treg cells among thymic mature CD4 single-positive cells, whereas Foxo1-deficient Foxp3+ Treg cells expanded in the peripheral lymphoid organs. However, such Foxp3+ Treg cells were nonfunctional in vivo, suggesting that the autoimmunity associated with Foxo1 deficiency in CD4+ T cells could be attributed to impaired function of Foxp3+ Treg cells. Notably, whereas the Foxp3 expression was nearly normal in Foxo1-deficent Treg cells, their expression of Treg-associated genes, such as CD25 and CTLA-4, were substantially reduced. Indeed, by chromatin immunoprecipitation, Foxo1 was shown to bind to the upstream of the transcription initiation site of the Ctla4 gene, and the Foxo binding element was required for full expression of CTLA-4. Recently, Ouyang et al. (2010) also reported that mice with T cell-specific deletion of both Foxo1 and Foxo3 developed fatal systemic inflammatory disease due in part to functional defect in Foxp3+ Treg cells. They showed that Foxo1 and Foxo3 directly bind to the Foxp3 promoter region and transactivate its promoter activity in a Foxo1 binding sequence specific manner. Thus, these reports together indicate that Foxo family transcription factors are required for appropriate control of the expression of Foxp3 and its target genes and that impairment in this Foxo-dependent gene expression in Foxp3+ Treg cells hampers their function and thereby produces autoimmunity.
One feature of the Foxo family transcription factors is that they have functional redundancy between their isoforms. Dejean et al. (2009) and Hosaka et al. (2004) reported that Foxo3-deficient mice showed no significant immunological abnormalities, such as spontaneous autoimmunity. Foxo3 deficiency did not alter the number or the proportion of activated or effector-memory T cells in the spleen and the lymph nodes. Moreover, T cells purified from Foxo3−/− mice showed no defect in proliferation and survival after in vitro stimulation. These results suggest that a loss of Foxo3 alone is not sufficient to elicit manifestations of T cell activation or autoimmunity. However, double-deficient mice produced by crossing Cd4-Cre Foxo1f/f mice with Foxo3-deficient mice developed severe systemic autoimmunity accompanying splenomegaly and lymphadenopathy (Kerdiles et al., 2010). Furthermore, retention of only one allele of either Foxo1 or Foxo3 in T cells was sufficient to prevent any major defects in Treg cell differentiation, contrasting with a marked reduction of thymic Treg cells in Foxo1−/−Foxo3−/− mice to approximately 50% of wild-type mice (Ouyang et al., 2010). These findings collectively indicate a redundancy in the function of Foxo1 and Foxo3 for the control of thymic Treg cell development and consequently for T cell homeostasis.
Transforming growth factor-β (TGF-β), which has pleiotropic effects, depending on cell types, induces Foxp3 expression in antigen-stimulated naive T cells. The phenotype of TGF-β-deficient or TGF-β receptor I-deficient mice closely resembles that of Foxp3-deficient mice; all these mutant strains develop lethal autoimmunity by 3–4 weeks of age. Kerdiles et al. (2010) showed that induction of TGF-β-induced Treg (iTreg) cells was highly impaired when T cells from tamoxifen-treated ER-Cre Foxo1f/f mice were stimulated by TGF-β, suggesting that Foxo1 is necessary for Foxp3 induction in iTreg cell differentiation. Moreover, TCR stimulation elicited an increase in the expression of T-bet, a key transcription factor for Th1 cell differentiation, in both wild-type and Foxo1-deficient T cells, whereas addition of TGF-β diminished T-bet expression in wild-type but not Foxo1-deficient T cells. These data indicate that Foxo1 is required for TGF-β-induced Treg cell differentiation, at least in part, via downregulation of T-bet. Harada et al. (2010) also showed that TGF-β-induced Foxp3 expression was impaired in CD4+ T cells from Cbl-b-deficient mice. Cbl-b-deficient T cells displayed augmented Foxo3 phosphorylation; further, forced expression of Foxo3 rescued their TGF-β-dependent Foxp3 expression. A Foxo3 binding motif is present in a proximal region of the Foxp3 promoter and was shown to be required for Foxp3 expression. Collectively, these studies have revealed that Foxo transcription factors promote the transcription of the Foxp3 gene in iTregs ([Kerdiles et al., 2010], [Harada et al., 2010] and [Ouyang et al., 2010]).
Regulation of Foxo transcriptional activity is mainly dependent on the phosphorylation of the Foxo proteins via PI3K-Akt pathway. Binding of growth factors to their receptors initiates PI3K and Akt activation, followed by Foxo phosphorylation, leading to inactivation of Foxos. The mammalian target of rapamycin (mTOR) is also one of the downstream targets of Akt. Recent studies ([Haxhinasto et al., 2008] and [Sauer et al., 2008]) have documented that mTOR forms the PI3K-Akt-mTOR axis in regulating Foxp3 expression. The involvement of mTOR in the differentiation of iTreg cells was further supported by the finding that T cells lacking mTOR kinase differentiate into iTreg cells by TCR stimulation alone in the absence of TGF-β. It is therefore plausible that PI3K-Akt signaling might suppress the Foxp3 expression via mTOR activation and Foxos inactivation.
Collectively, the studies by Kerdiles et al. and others strongly support the notion that Foxo1 and Foxo3 have critical overlapping roles in the development of thymic-derived natural Treg and TGF-β-induced iTreg cells. Kerdiles et al. (2009) previously reported that Foxo1 regulates the homeostasis and life span of naive T cells. Yet it remains unclear how Foxos play different roles when they are in naive or Treg cells. Furthermore, several interacting partners with Foxos have been identified, whereas the mechanisms by which Foxos regulate their target genes in Treg cells still remain unknown. Recent studies have shown that a functional NFAT binding site lies in the Foxp3 enhancer region, with close proximity to the Smad3 binding motif (Tone et al., 2008), and the Runx transcription factors are critically involved in induction and suppressive function of Treg cells through the direct binding to the Foxp3 gene (Kitoh et al., 2009). Taken together, Treg development via Foxp3 induction is a complex event controlled by a variety of transcription factors, including Foxo family transcription factors. Further study is required to decipher the complex transcriptional network for regulating Foxp3 expression.
References
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Corresponding author

Volume 33, Issue 6, 14 December 2010, Pages 835-837

quarta-feira, 29 de dezembro de 2010

O ano de 2010 não foi um bom ano para a economia do mundo. The Economist


A revista The Economist publicou o ano de 2010 em nove gráficos. O Brasil ao lado da China e India, é mencionado em um dos gráficos revela que houve crescimento no PIB (GDP) e no emprego, ao contrário da maioria dos países



Artigo da Newsweek faz comentários grosseiros sobre desigualdade de renda no Brasil


Para comentar a política de Obama sobre a desigualdade de renda americana o autor faz um pararelo infeliz com a desigualdade no Brazil.



Obama and Income Inequality: No New Brazils!

We're going to be hearing a lot about income inequality over the next few years. It may be an abstract concept, but it gets hits like Sarah Palin and attracts grant money like Cory Booker. Tim Noah's series on the subject was (rightly) so popular he got a book contract out of it. Jacob Weisberg's piece, in which he declares (plausibly) that Obama is losing the "war on inequality" has been up for a few hours and is already a magnet for impassioned comments.
There are two big questions to ask liberal opponents of income inequality. 1) What, exactly, is it about greater economic inequality that's so bad? and 2) What you gonna do about it? Let's take the first question.* Noah wrestles with it and concludes
I do not wish to live in a banana republic. There is a reason why, in years past, Americans scorned societies starkly divided into the privileged and the destitute. They were repellent.
Weisberg's answer also has a Latin flavor:
Moving toward an income distribution like Brazil's threatens individual happiness, social peace, and American values.
My own answer is that we care about income inequality because it corrodes social equality—i.e., whether we respect each other as equals. But if that's the reason, I'd argue, there are other methods (e.g., national service, a national health care system, safe and popular public spaces) that can directly give us more social equality than longshot liberal efforts to indirectly affect social equality by trying to "reverse" a "decades long trend toward income inequality" that is powered by fundamental shifts in technology and trade. **
But, hey, whatever. Let's assume the problem is income inequality. And none of us wants Brazil.
The question is then what makes Brazil Brazil. Is it wild riches at the top, or extreme poverty at the bottom? It seems pretty obvious, from what little I know of Brazil, that the problem is the bottom, not the top. We worry about Brazil because of the favelas, the huge impoverished shantytowns, and the crime coming out of them. We worry because it's hard to believe that if you're a poor Brazilian squatting in a shanty you can think of yourself as the social equal of a tycoon across town. And across town, thanks to all that crime, it seems impossible to lead a normal, American-style socially-egalitarian middle class life, at least without a full-time bodyguard. You're not about to go sit in the cheap seats at a soccer match or wander near your local favela while shopping. I had an affluent Brazilian friend who moved to New York City and would only consider living in Trump buildings, on the grounds that only they would have adequate security for someone of her class. I finally convinced her that no, this was America. You could really live almost anywhere you wanted. You didn't need a guard with a gun on every floor. And you could walk around.
If you're worried about incomes at the bottom, though, one solution leaps out at you. It's a solution that worked, at least in the late 1990s under Bill Clinton, when wages at the low end of the income ladder rose fairly dramatically. The solution is tight labor markets. Get employers bidding for scarce workers and you'll see incomes rise across the board without the need for government aid programs or tax redistribution. A major enemy of tight labor markets at the bottom is also fairly clear: unchecked immigration by undocumented low-skilled workers. It's hard for a day laborer to command $18 an hour in the market if there are illegals hanging out on the corner willing to work for $7. Even experts who claim illlegal immigration is good for Americans overall admit that it's not good for Americans at the bottom. In other words, it's not good for income equality.
Odd, then that Obama, in his "war on inequality," hasn't made a big effort to prevent illegal immigration--or at least to prevent illegal immigrration from returning with renewed force should the economy recover. He hasn't, for example, pushed to make it mandatory for employers to use the "E-Verify" system, or some other system, to check the legality of new hires, preferring to hold that reform hostage (sorry!) in order to try and achieve a larger "comprehensive" bill that included a conditional amnesty for the 11 or so million illegals already here. (In Washington, if something's obviously desirable that means it's a bargaining chip.) True, Obama has tried to make a big deal of his administration's deportation numbers, but only as a nose-holding effort to placate the right sufficiently to get a mass legalization bill through. And the deportation numbers themselves are suspect.
I'd argue Obama's main effort on immigration would, in fact, have made the inequality problem at the bottom worse. A "comprehensive" bill would almost certainly have attracted new illegals, but the efforts to stop them at the border might well have failed, as they failed after a similar 1986 bill. The result of that failure has been a looser labor market at the bottom. Lower unskilled wages. Even the emergence of favela-like shantytowns in California. You want Brazil? Obama's 2009-2010 immigration plan would bring us Brazil. Obama was putting coalition politics--pleasing Latino voters, and especially Latino politicians--over economics, at least egalitarian economics.
The good news is that now, because his immigration reform failed, Obama has a potential money-equalizing solution in sight. Republicans in the House are going to propose various anti-undocumented "enforcement" efforts, including widespread use of E-Verify, designed to prevent the flooding of the unskilled labor market. All Obama has to do is go along. He can go along reluctantly and tell his Latino coalition partners that he really hates having to sign an E-Verify bill, the way he hated having to sign an extension of the Bush tax cuts for the top brackets. Or he can actually transcend his coalition and tell them, maybe even convince them, that they're wrong, that controlling the border ("Enforcement First") is a) the best way to boost wages at the bottom and b) the only way to eventually set the stage for legalization.
You never know, but there are approximately zero signs that Obama is ready to engage in the second type of leadership. If he has to have egalitarian policies pushed on him by Republican committee chairman, to what extent are he and the Democrats fighting a "war on inequality"?
__________
* On the second question, suffice it to say I think Obamans were in fantasyland if they actually thought that (in David Leonhardt's words) raising $100 billion in annual taxes on the rich, "increasing federal college aid," and reducing health insurance premiums--the main pro-equality provisions in Obama's initial budget—could "reverse the rapid increase in economic inequality over the last 30 years".
** Weisberg's solution ("the key to combating inequality") is "upgrading the education and skills of American workers." This is everybody's favorite answer, but you have to almost consciously avoid thinking about it not to see the problems. 1) It takes a really long time--many decades at plausible levels of "human capital" investment. 2) Not everyone can have their education and skills upgraded at will. Some people are less upgradeable than others and some are not upgradeable at all. 3) The rise in income inequality hasn't been just a rise in the extra pay earned by those with college degrees. There is also the "star" pheonomenon in which the most talented of a group of similarly-educated people take home increasingly bigger and bigger checks. It's certainly not clear that sending everyone to college will make everyone a star; it might help proleterianize some professions, something that is arguably happening to lawyers and doctors; 4) Computers and the Internet are getting better at taking away or outsourcing the jobs of the skilled; 5) A truly meritocratic society in which everyone acquired as many valuable skills as they could would probably be a social egalitarian hell, with smart people on top and stupid people on the bottom and everybody all too aware of this. Weisberg's education solution is actually toxic to the ultimate goal of income equality, which is (to quote one of Noah's sources) society in which we are "used to working together and respecting each other as equals" (i.e. social equality).
___________________________

You never know, but there are approximately zero signs that Obama is ready to engage in the second type of leadership. If he has to have egalitairan policies pushed on him by Republican committee chairman, to what extent are he and the Democrats fighting a "war on inequality"?
__________
* On the second question, suffice it to say I think Obamans were in fantasyland if they actually thought that (in David Leonhardt's words) raising $100 billion in annual taxes on the rich, "increasing federal college aid," and reducing health insurance premiums--the main pro-equality provisions in Obama's initial budget—could "reverse the rapid increase in economic inequality over the last 30 years".
** Weisberg's solution ("the key to combating inequality") is "upgrading the education and skills of American workers." This is everybody's favorite answer, but you have to almost consciously avoid thinking about it not to see the problems. 1) It takes a really long time--many decades at plausible levels of "human capital" investment. 2) Not everyone can have their education and skills upgraded at will. Some people are less upgradable than others and some are not upgradeable at all. 3) The rise inincome inequality hasn't been just a rise in the extra pay earned by those with college degrees. There is also the "star" pheonomenon in which the most talented of a group of similarly-educated people take home increasingly bigger and bigger checks. It's certainly not clear that sending everone to college will make everyone a star; it might help proleterianize some professions, something that is arguably happening to lawyers and doctors; 4) Computers and the Internet are getting better at taking away or outsourcing the jobs of the skilled; 5) A truly meritocratic society in which everyone acquired as many valuable skills as they could would probably be a social egalitairan hell, with smart people on top and stupid people on the bottom and everybody all too aware of this. Weisberg's education solution is actually toxic to the ultimate goal of income equality, which is (to quote one of Noah's sources) society in which we are "used to working together and respecting each other as equals" (i.e. social equality).
___________________________

segunda-feira, 27 de dezembro de 2010

Nova York under ice

Não reclame do calor. O frio em NY city hoje é muito ruim e amanhã quando a neve derreter será ainda pior

fotos NY times














VEGF solúvel em melanoma


EXPRESSION OF THE SOLUBLE VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1 IN CUTANEOUS MELANOMA: ROLE IN TUMOUR PROGRESSION
F. Ruffini1, C. M. Failla2, A. Orecchia2, M. R. Bani3, A. S. Dorio4, C. Fortes5, G. Zambruno2, G. Graziani4, R. Giavazzi3, S. D’Atri1, P. M. Lacal1
DOI: 10.1111/j.1365-2133.2010.10200.x

Copyright © 2010 British Association of Dermatologists
Issue
British Journal of Dermatology
Accepted Article (Accepted, unedited articles published online for future issues)
Keywords:
sVEGFR-1;VEGF-A;angiogenesis;melanoma progression;angiogenic switch
Abstract
Background:  Vascular endothelial growth factor (VEGF)-A, placenta growth factor (PlGF), and their corresponding membrane receptors, are involved in autocrine and paracrine regulation of melanoma growth and metastasis. Besides the membrane receptors, a soluble form of the VEGFR-1 (sVEGFR-1) has been identified, that behaves both as a decoy receptor, sequestering VEGF-A and PlGF, and as an extracellular matrix (ECM) molecule, promoting endothelial cell adhesion and migration through the interaction with α5β1 integrin.

Objectives:  To analyze whether sVEGFR-1 plays a role during melanoma progression.

Methods:  sVEGFR-1 expression was evaluated in a panel of 36 melanoma cell lines and 11 primary human melanocyte cultures by quantitative real-time PCR analysis and in specimens of primary or metastatic melanoma lesions from 23 patients by immunohistochemical analysis.

Results:  sVEGFR-1 expression was highly up-regulated in melanoma cell lines with respect to human melanocytes. Interestingly, cell lines obtained from cutaneous metastases showed a significant reduction of sVEGFR-1 expression, as compared with cell lines derived from primary tumours. These results were confirmed by immunohistochemical analysis of sections from primary skin melanomas and the corresponding cutaneous metastases, suggesting that modulation of sVEGFR-1 expression influences ECM invasion by melanoma cells and metastasis localization. Moreover, we provide evidence that adhesion of melanoma cells to sVEGFR-1 is favoured by the activation of a VEGF-A/VEGFR-2 autocrine loop.

Conclusions:  Our data strongly suggest that sVEGFR-1 plays a role in melanoma progression and that low sVEGFR-1:VEGF-A and sVEGFR-1:mVEGFR-1 ratios might predict a poor outcome in melanoma patients.

Como funciona os PPARy em macrófagos - Immunity


Figure 1.
IL-4 Facilitates PPARγ-Dependent Gene Expression through STAT6 Signaling
In macrophages, PPARγ binds to the adipocyte PPAR response element (AdipoPPRE) as well as the macrophage PPAR response element (MacPPRE) in the Fabp4 gene (encoding aP2). Maximal PPARγ activity and expression of aP2 is dependent on STAT6 binding to a STAT6 response element (S6RE) adjacent to the MacPPRE.


Licensing PPARγ to Work in Macrophages
Claudio J. Villanueva1 and Peter Tontonoz1, ,
1 Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA

The mechanisms that direct cell-type-specific peroxisome proliferator-activated receptor (PPAR) gene programs are poorly understood. In this issue of Immunity, Szanto et al. (2010) identify signal transducer and activator of transcription 6 as a transcriptional switch that licenses PPARγ-dependent gene expression in macrophages and dendritic cells.

Macrophages are central components of the innate immune system that are critical for host defense. Found in almost all tissues, they exhibit wide heterogeneity and acquire a variety of functional phenotypes depending on the external milieu. For example, dendritic cells and macrophages present foreign antigens and coordinate inflammatory responses triggered by microbial pathogens through the production of proinflammatory factors. In other contexts, they clear apoptotic cells and facilitate tissue remodeling and resolution of inflammation through production of anti-inflammatory mediators. Classical activation of macrophages (M1 phenotype) is induced by T helper 1 (Th1) cell inflammatory cytokines such as tumor necrosis factor α (TNFα) and interferon-γ (IFNγ) and by pathogen activation of Toll-like receptors (TLRs). M1 activation leads to a coordinated inflammatory response that primes cells to deal with pathogens. Alternative activation of macrophages (M2 phenotype) can be triggered by Th2 cell-activated T cells, mast cells, basophils, eosinophils, or macrophages through release of the cytokines interleukin (IL)-4 or IL-13. Alternative activation has been implicated in parasitic infections, allergy, tissue repair, and inflammation. Although it is useful to lump macrophages into the M1 and M2 categories for the purposes of broad discussion, it is likely that a continuum of phenotypes between these rigid categories is adopted by endogenous macrophages, depending on the cellular context.
In this issue of Immunity, Szanto et al. (2010) elucidate a mechanism whereby alternative macrophage activation leads to enhanced peroxisome proliferator-activated receptor γ (PPARγ)-dependent gene expression. PPARγ is a ligand-activated transcription factor that was originally characterized as a master regulator of adipogenesis. PPARs form obligate heterodimers with retinoid X receptors (RXRs) that bind to cis-regulatory elements (PPREs) found in proximal promoters, introns, or distal regions of their target genes. In adipose cells, PPARγ regulates the expression of genes involved in differentiation, lipid uptake, and triglyceride storage. PPARγ is also the target of a popular class of antidiabetic drugs, thiazolidinediones, that act as direct ligands of the receptor.
In addition to adipose tissue, PPARγ is highly expressed in macrophages and is induced during monocyte differentiation and dendritic cell maturation. It has been recognized for several years that the gene expression programs induced by PPARγ ligands in adipocytes and macrophages are only partially overlapping, raising the question of how cell-type specificity is accomplished. Lazar and colleagues have recently reported that binding sites for the transcription factor PU.1 are present, together with PPREs, in many macrophage-expressed PPARγ target genes (Lefterova et al., 2010). This characteristic distinguishes them from adipocyte-selective target genes, which commonly have C/EBPα binding sites adjacent to the PPREs.
The molecular basis for differential engagement of PPARγ responses between different types of macrophages and dendritic cells has also been an important question in the field. Glass and colleagues reported a number of years ago that the Th2 cell cytokine IL-4 was a strong inducer of PPARγ expression in macrophages (Huang et al., 1999). Subsequent studies reported that an active PPARγ pathway is a prominent feature of alternatively activated (M2) macrophages and that M2-type responses were compromised in the absence of PPARγ expression (Odegaard et al., 2007). PPARγ expression is important for the full expression of certain genes characteristic of M2 macrophages, especially the gene encoding arginase I, a direct PPAR target ([Odegaard et al., 2007] and [Gallardo-Soler et al., 2008]). However, the degree to which PPARγ activity is required for the establishment of broader IL-4 responses and the various biological functions of alternatively activated macrophages has continued to be an active area of investigation (Marathe et al., 2009). In particular, the transcriptional underpinnings of IL-4-PPARγ crosstalk in alternatively activated macrophages have remained poorly understood.
Szanto et al. (2010) began by investigating how the PPARγ pathway was altered in various types of macrophages and dendritic cells. They found that activation of macrophages with IL-4 drove the expression of PPARγ itself and enhanced target gene expression in response to the PPARγ ligand rosiglitazone. In contrast, classical activation of the cells with IFNγ, TNFα, or lipopolysaccharide (LPS) inhibited the response to rosiglitazone, despite the fact that increased PPARγ expression was also observed with LPS treatment. Crosstalk between IL-4 and PPARγ signaling was further supported by global gene expression analysis. Remarkably, the authors found that rosiglitzone induced 635 genes in the presence of IL-4 but only 120 genes in the absence of IL-4. Moreover, both the magnitude of induction and the number of genes regulated by PPARγ were affected by IL-4. Thus, robust activation of PPARγ signaling in macrophages and dendritic cells was highly dependent on IL-4 stimulation, and this could not simply be explained by differences in PPARγ expression. Importantly, the requirement for IL-4 in PPARγ responses was also observed in mouse and human macrophages as well as in dendritic cells. These findings suggested the existence of one or more transcription factors that “gate” or “license” the PPARγ response in myeloid cells.
The authors went on to address the reciprocal question of the degree to which PPARγ was required for the gene expression response to IL-4. In contrast to the strong requirement of PPARγ target genes for IL-4 costimulation, the IL-4 transcriptome was modestly affected in the absence of the gene encoding PPARγ in macrophages. For example, induction of the alternative activation markers YM1 or FIZZ1 by IL-4 proceed normally in wild-type or PPARγ-deficient peritoneal or bone marrow-derived macrophages.
To determine how IL-4 signaling was potentiating PPARγ activity on a molecular basis, Szanto et al. (2010) employed pharmacological inhibitors to interrogate various signaling pathways known to act downstream of the IL-4 receptor. The finding that WHI-P131, an inhibitor of the Janus kinase (Jak) 3 pathway, antagonized the induction of the lipid-binding protein aP2 by rosiglitazone led the authors to hone in on signal transducer and activators of transcription 6 (STAT6), a transcription factor known to mediate IL-4 signaling in macrophages. Using macrophages that were genetically deficient in STAT6 expression, the authors were able to show that PPARγ signaling in IL-4-treated macrophages was highly dependent on STAT6. For example, PPARγ target genes such as Fabp4 (encoding aP2) and Angptl4 (encoding PGAR) showed a muted response to rosiglitazone in Stat6−/− compared to wild-type macrophages. Global transcriptional profiling confirmed that a majority of PPARγ-responsive genes required STAT6 for full activation in macrophages.
These findings led the authors to hypothesize that STAT6 might be regulating PPARγ target genes by binding to their regulatory sequences directly. This idea was validated initially by coexpressing STAT6 and PPARγ in transient transfection assays along with an Fabp4-luciferase reporter. Promoter activity was additively responsive to STAT6 and PPARγ, consistent with a direct effect on the Fabp4promoter. The authors then analyzed the Fabp4 gene to identify the response elements involved. Previous studies in adipocytes showed that PPARγ binds to a PPRE in the distal region of the Fabp4 enhancer, approximately 5.4 kb from the transcriptional start site (Tontonoz et al., 1994). Interestingly, Szanto et al. (2010) identified an additional, previously unknown response element, which they termed MacPPRE to distinguish it from the adipocyte PPRE. Moreover, this regulatory region contained a highly conserved STAT6 binding site adjacent to the MacPPRE (Figure 1). Mutation of the MacPPRE or STAT6 element eliminated the ability of IL-4 to facilitate activation of the Fabp4 promoter.

An important remaining question was whether PPARγ or STAT6 could be localized to the region of the MacPPRE in the endogenous Fabp4 gene in macrophages. To address this possibility, the authors employed chromatin immunoprecipitation (ChiP) assays using antibodies for STAT6 and PPARγ. Indeed, PPARγ was shown to occupy both the adipocyte PPRE and the identified MacPPRE in macrophages. Unexpectedly, however, STAT6 was enriched in the region of the adipocyte PPRE as well as the region of the MacPPRE (which contains the STAT6 element). Although this finding may simply reflect the limited resolution of the ChiP assay, a more provocative interpretation is that STAT6 may interact with PPARγ without having to bind to DNA, perhaps serving as a coactivator in macrophages. In support of this idea, the authors showed that STAT6 could be pulled down with purified PPARγ protein in biochemical interaction assays. Finally, consistent with the common requirement of many macrophage PPARγ target genes for IL-4 signaling, ChIP assays revealed diminished PPARγ occupancy on the Angptl4, Cd36, Fabp4, and Scd1 promoters in STAT6-deficient macrophages.
In summary, Szanto et al. (2010) have outlined a role for the IL-4-dependent transcription factor STAT6 as a licensing factor for PPARγ activity in macrophages and dendritic cells. These studies provide additional mechanistic support for the emerging concept that cell-type-specific gene regulation is dependent on a combinatorial code of transcriptional regulators. In addition, the work brings insight into how this code is implemented on specific gene promoters. These findings also extend and clarify prior work by positioning PPARγ downstream rather than upstream of IL-4 in the alternative macrophage activation cascade (Odegaard et al., 2007). Furthermore, the identities of the genes coregulated by IL-4 and PPARγ are suggestive of a discrete role for PPARγ signaling in a transcriptional program for handling lipids after phagocytosis of apoptotic cells or parasites. In agreement with this possibility, recent studies have reported a role for the related nuclear receptor PPARδ in phagocytic responses (Mukundan et al., 2009).
Several questions are raised by the findings of Szanto et al. (2010) that will undoubtedly be the focus of additional research in the coming years. For example, what is the role of PPAR-dependent gene expression in the different functions of alternatively activated macrophages and dendritic cells in various biological contexts? What is the relative importance of lipid metabolic and inflammatory gene expression in these settings? What is the natural ligand for PPARγ in macrophages and how does this fit with the biology of IL-4? Lastly, given the centrality of metabolism and inflammation in human disorders such as atherosclerosis and diabetes, it will be important to determine the relevance of PPARγ-STAT6 interaction for disease pathogenesis, immunological responses, and therapeutic intervention.
References
Gallardo-Soler et al., 2008 A. Gallardo-Soler, C. Gómez-Nieto, M.L. Campo, C. Marathe, P. Tontonoz, A. Castrillo and I. Corraliza, Mol. Endocrinol. 22 (2008), pp. 1394–1402. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (17)
Huang et al., 1999 J.T. Huang, J.S. Welch, M. Ricote, C.J. Binder, T.M. Willson, C. Kelly, J.L. Witztum, C.D. Funk, D. Conrad and C.K. Glass, Nature 400 (1999), pp. 378–382. View Record in Scopus | Cited By in Scopus (466)
Lefterova et al., 2010 M.I. Lefterova, D.J. Steger, D. Zhuo, M. Qatanani, S.E. Mullican, G. Tuteja, E. Manduchi, G.R. Grant and M.A. Lazar, Mol. Cell. Biol. 30 (2010), pp. 2078–2089. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7)
Marathe et al., 2009 C. Marathe, M.N. Bradley, C. Hong, L. Chao, D. Wilpitz, J. Salazar and P. Tontonoz, J. Lipid Res. 50 (2009), pp. 214–224. View Record in Scopus | Cited By in Scopus (6)
Mukundan et al., 2009 L. Mukundan, J.I. Odegaard, C.R. Morel, J.E. Heredia, J.W. Mwangi, R.R. Ricardo-Gonzalez, Y.P. Goh, A.R. Eagle, S.E. Dunn and J.U. Awakuni et al., Nat. Med. 15 (2009), pp. 1266–1272. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (19)
Odegaard et al., 2007 J.I. Odegaard, R.R. Ricardo-Gonzalez, M.H. Goforth, C.R. Morel, V. Subramanian, L. Mukundan, A. Red Eagle, D. Vats, F. Brombacher, A.W. Ferrante and A. Chawla, Nature 447 (2007), pp. 1116–1120. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (229)
Szanto et al., 2010 A. Szanto, B.L. Balint, Z.S. Nagy, E. Barta, B. Dezso, A. Pap, L. Szeles, S. Poliska, M. Oros and R.M. Evans et al., Immunity 33 (2010), pp. 699–712 this issue. Article | PDF (935 K) | View Record in Scopus | Cited By in Scopus (1)
Tontonoz et al., 1994 P. Tontonoz, E. Hu, R.A. Graves, A.I. Budavari and B.M. Spiegelman, Genes Dev. 8 (1994), pp. 1224–1234. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (1257)



- Posted using BlogPress from my iPad

domingo, 26 de dezembro de 2010

O farol transformado em gelo


Aconteceu nos Estados Unidos com temperaturas congelantes o farol visto na primeira foto foi transformado em bloco de gelo, nas duas fotos abaixo








Naked Lighthouse
Photograph by Ella Spiri, My Shot

Seen in a September 2008 picture taken by National Geographic My Shot user Ella Spiri, Cleveland's West Pierhead Lighthouse looks much like any other lighthouse. But come winter, it and other Great Lakes lighthouses sometimes turn into fairy castles, birthday cakes, or whatever wintry description best fits.

Ice buildup on Great Lakes lighthouses are not uncommon. "You're going to get ice buildup whenever the weather is this way," Degener said. But the 2010 freeze-out happened much earlier, because frigid temperatures arrived sooner than usual.

The extent of the freezing in 2010 is also exceptional. It's rare for ice to coat a lighthouse so thoroughly that the light is no longer visible.

(Read about the "incredible shrinking Great Lakes.")

sábado, 25 de dezembro de 2010

Energia Renovável no Brasil - Natureza




Brazil's renewable energy success

Allan Kardec Duailibe
Nature 468, 1041 (23 December 2010) doi:10.1038/4681041b
Published online 22 December
Brazil's advanced energy matrix is starting to pay off: 47.3% of its primary energy is now renewable. The world average is still around 13%.

Last year, Brazil produced 244 million TOE (tonnes of oil equivalent), of which 42.6% came from oil and coal, and the rest from sugar cane (18.2%), hydropower (15.2%), biomass (13.9%), natural gas (8.7%) and uranium (1.4%).

Ethanol accounted for 18.8% of fuel usage, and natural gas and biodiesel for 3.3%. In just 2 years, Brazil has reached its target of 5% biodiesel additive in diesel. Ethanol is set to overtake petrol as fuel, thanks to flexible-fuel engines that use both at the same time. These account for 90% of small-car sales in the past 2 years.

The country is developing the technology for 'green' petrol and diesel production from sugar cane and agricultural waste, and from the castor-oil residue generated during biodiesel manufacture.

Brazil's government estimates that only about 2.5% of arable land will be needed to meet the ethanol demand forecast for 2017 (today this is 1.4%). Burning of sugar-cane pulp (bagasse) is expected to supply 15% of Brazil's electricity by 2017, comparable to that being generated by the Itaipu hydropower plant on the Brazil–Paraguay border.- Posted using BlogPress from my iPhone

quinta-feira, 23 de dezembro de 2010

Feliz Natal e Um novo ano novo- 2011 será unico

Feliz Um ano novo, Novo mesmo em tudo

Esses são nossos votos aos amigos e integrantes do LASP

Receita de Ano Novo

Para você ganhar belíssimo Ano Novo
cor de arco-íris, ou da cor da sua paz,
Ano Novo sem comparação com todo o tempo já vivido
(mal vivido talvez ou sem sentido)
para você ganhar um ano
não apenas pintado de novo, remendado às carreiras,
mas novo nas sementinhas do vir-a-ver,
novo até no coração das coisas menos percebidas
(a começar pelo seu interior)
novo, espontâneo, que de tão perfeito se nota,
mas com ele se come, se passeia,
se ama, se compreende, se trabalha,
você não precisa beber champanha ou qualquer outra
birita,
não precisa expedir nem receber mensagens
(planta ou recebe mensagens? passa telegramas?).
Não precisa fazer lista de boas intenções
para arquivá-las na gaveta.
Não precisa chorar de arrependido
pelas besteiras consumadas
nem parvamente acreditar
que por decreto da esperança
a partir de janeiro as coisas mudem
e seja tudo claridade, recompensa,
justiça entre os homens e as nações,
liberdade com cheiro e gosto de pão matinal,
direitos respeitados, começando
pelo direito augusto de viver.
Para ganhar um ano-novo que mereça este nome,
você, meu caro, tem de merecê-lo,
tem de fazê-lo de novo, eu sei que não é fácil,
mas tente, experimente, consciente.
É dentro de você que o Ano Novo
cochila e espera desde sempre.

Carlos Drumond de Andrade

terça-feira, 21 de dezembro de 2010

Burocracia na Ciência Brasileira _ Sérgio Resende

Burocracia, só não, paga-se imposto pelos reagentes, restrição de importação pela ANVISA etc.
Essa reportagem é a opinião do cientista no governo, portanto ele em parte defende e faz uma critica reservada.
A situação hoje é melhor do que antes, mas muito aquém do necessário da que se observa nos países mais desenvolvidos e emergentes.

Burocracia torna a ciência brasileira menos competitiva


MINISTRO DA CIÊNCIA FAZ BALANÇO DE GESTÃO DE MAIS DE CINCO ANOS E DIZ QUE META DEVE SER FORTALECER CULTURA DE PESQUISA EM EMPRESAS


Leo Caldas/Folhapress
Sérgio Rezende, ministro da Ciência e Tecnologia, na UFPE, onde leciona

SABINE RIGHETTI
DE SÃO PAULO

O físico carioca Sérgio Rezende deixará em 31 de dezembro o MCT (Ministério da Ciência e Tecnologia), que esteve sob seu comando por mais de cinco anos.
Em entrevista exclusiva à Folha, ele reconhece que, apesar dos avanços de sua gestão, a burocracia ainda é um dos grandes inimigos dos cientistas brasileiros. Também defendeu a escolha do petista Aloizio Mercadante como seu sucessor: "Certamente pode ter um papel de influência no governo". Leia os melhores trechos da conversa abaixo.



Folha- O sr. está saindo de uma gestão considerada positiva. Isso é raro...
Sérgio Rezende -
Eu só espero que as pessoas não fiquem com saudades de mim [risos]. Tivemos mais recursos e, acompanhando isso, uma atuação mais forte do governo federal em incentivar e apoiar a pesquisa e inovação nas empresas.
Isso é uma mudança grande. Nossa política científica sempre foi desvinculada da política industrial -que, por sua vez, teve seus altos e baixos. Não havia acontecido até agora uma articulação entre ciência e indústria. Estamos aprendendo a fazer isso, mas avançamos muito.

Ter 1,3% do PIB destinado à ciência é suficiente?
Passar de 1% foi mudar de patamar. Tínhamos planejado chegar a 1,5% do PIB e chegamos a 1,3%. No entanto, em números absolutos, nós atingimos a meta, porque o PIB do Brasil cresceu muito e continua crescendo.

Mas qual seria o ideal?
Os países desenvolvidos têm em média 2,5% do PIB investido em ciência. Mas esses países têm muito mais cientistas: são dois cientistas para cada 10 mil habitantes. Nós temos um pesquisador para 10 mil pessoas. Se tivéssemos mais recursos, eles não seriam utilizados.
Precisamos formar mais gente, e isso é um processo gradual. A ideia é que a gente chegue a 2022 com dois pesquisadores para cada 10 mil habitantes e com 2,5% do PIB em ciência.

Ainda há barreiras por parte de quem acha que dinheiro público não deve ser gasto com ciência nas empresas?
Existe um pouco. Essas vozes estão ficando isoladas. Felizmente nós estamos passando dessa fase. Há 20 anos se dizia que o dinheiro público deve ficar na universidade e que empresa não deveria fazer pesquisa. Dizia-se que ciência não combina com lucro. Isso é uma bobagem.

Esse tipo de crítico também costuma dizer que não dá para fazer "Big Science" [ciência cara e de grande porte] num país que ainda tem gente passando fome.
A ciência feita com intensidade, com aplicações, contribui de maneira eficaz para resolver os problemas sociais.
O melhor exemplo que temos é da Coreia do Sul, a qual, na década de 1970, era mais subdesenvolvida que o Brasil. Eles investiram em tecnologia e inovação e, com isso, o país tirou milhões de pessoas da pobreza.

Qual foi o principal desafio da sua gestão?
Nós tivemos um problema com o excesso de burocracia. Alguns desvios que aconteceram em fundações de amparo à pesquisa fizeram o TCU [Tribunal de Contas da União] tornar a execução de recursos muito mais difícil.
Hoje a burocracia é um dos entraves para a realização da atividade de pesquisa no Brasil de maneira mais tranquila. É uma burocracia para se usar os recursos, para explicar como usou. Um cientista brasileiro enfrenta muito mais burocracia do que um europeu para fazer o mesmo trabalho, e isso diminui a competitividade.
Nós conseguimos simplificar o procedimento de importação, mas ainda é bem mais difícil um pesquisador daqui comprar um equipamento de fora do que um pesquisador de outro país.
Nos outros lugares é assim: o pesquisador quer comprar um equipamento para fazer uma pesquisa e compra. Aqui não pode, tem sempre de fazer licitação e comprar o mais barato.
Eu decidi sair antes do resultado da eleição. Estou há dez anos consecutivos em atividade de gestão. No momento, quero me dedicar à atividade científica e não à gestão. A gestão do cotidiano, dos problemas, das pessoas, das confusões -isso é algo que desgasta.
Nós demos um salto no MCT, e eu acho que não conseguiria dar novo salto. Precisamos de novas ideias.

Mas o sr. já foi convidado para administrar alguma outra instituição?
Sim, já tive mais de um convite. Mas já disse que não quero mais ter atividade executiva nos próximos anos. Estou indo para Pernambuco [na UFPE].
Estou envolvido em nanotecnologia de materiais magnéticos, já tenho alguns trabalhos. Há dois pós-doutores publicando resultados interessantes, e estou sem tempo de me juntar a eles, de entender o problema, de fazer teoria. Pode ser que em dois anos em volte à gestão, mas agora eu quero ser cientista.

Aloizio Mercadante será um bom ministro no seu lugar?
Ele tem tudo para ser um bom ministro. É uma pessoa de visão larga, certamente pode ter um papel de influência no governo.

segunda-feira, 20 de dezembro de 2010

como se pode alterar a inflamação inibindo a adesão leucocitaria


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Moving targets: cell migration inhibitors as new anti-inflammatory therapies

Charles R Mackay1

Abstract
The pharmaceutical industry has targeted various types of molecules to subdue inflammatory diseases. Drugs that disrupt cell migration appear particularly promising in clinical trials and in many animal models of inflammatory disease. Cell migration inhibitors not only interfere with migration of cells to a tissue, but also can affect other necessary processes such as mediator release and angiogenesis. However, the question is whether drugs that target adhesion molecules or chemoattractant receptors will prove superior to drugs that target other molecular types. This review proclaims the virtues of targeting cell migration–related molecules for development of new anti-inflammatory and anti-tumor based drugs. It is likely that cell migration inhibitors will transform the way in which many human inflammatory diseases and cancers are treated.

Introduction
Despite the many billions of dollars that have been spent on immunological research, few effective anti-inflammatory drugs have emerged. An urgent need for new drugs exists, as many inflammatory diseases are inadequately responsive to current medications. Moreover, in developed countries, the incidence of some inflammatory diseases, such as asthma, has increased markedly over recent decades. The incidence of some autoimmune diseases, including type 1 diabetes, is also on the rise, further suggestive of links between inflammatory diseases and aspects of modern lifestyles1. The challenge for the development of new anti-inflammatory drugs has been to find appropriate targets that are essential in the inflammatory process but are mostly dispensable for host defense against pathogens.

The development of several new drugs is poised to revolutionize the treatment of inflammatory diseases. Therapeutics that selectively alter cell migration represent a particularly promising class of the new anti-inflammatory drugs. The basis for this optimism rests on several recent developments. The first is the proven efficacy of the first migration-inhibitory drug to be approved, the anti–4 integrin monoclonal antibody (mAb) natalizumab (Tysabri). This agent represents a breakthrough for the treatment of multiple sclerosis and Crohn's disease, by limiting T cell migration to an inflamed tissue, such as the central nervous system in multiple sclerosis. A second development has been the discovery of the many cell migration molecules required for development of different inflammatory responses and the demonstration in animal models that targeting these is a highly effective way to ameliorate inflammation. Finally, after a slow start, the pharmaceutical industry has developed potent and selective small molecule as well as mAb inhibitors for most of the important cell migration molecules, particularly the chemoattractant receptors. While adhesion molecules, such as the integrins, have generally been targeted by protein based drugs such as mAbs, chemoattractant receptors are G protein–coupled receptors (GPCRs) that are generally amenable to inhibition by organic small molecule drugs. The ability to take them orally makes small molecule inhibitors the drug of choice, yet mAbs also offer some distinct advantages.

Intervention points for cell migration inhibitors
Leukocyte extravasation usually occurs through a multistep process, involving first the selectins, then chemoattractant receptor signaling, followed by firm adhesion to vessel walls through the actions of integrins (Fig. 1). Thereafter, leukocytes migrate along chemotactic gradients, by means of chemoattractant receptor signaling and the actions of adhesion molecules, particularly integrins. Each of the molecular participants in this process—selectins, chemoattractants and integrins—has a fundamental and sequential role, such that inhibition of any given selectin, chemoattractant receptor or integrin could effectively inhibit leukocyte extravasation entirely. Selectin or integrin adhesion molecules are few, whereas the number of chemokines and other chemoattractants suggest that these latter molecules must be prominent in dictating the precise placement of leukocyte subsets. For instance, many of the functional subsets of T cells express the 4 integrin uniformly, but they differentially express a range of chemoattractant receptors such as CCR5, CCR6 and CXCR5. This provides opportunities, as well as pitfalls. If a drug targets a cell migration molecule too selectively, it might be ineffective.If it inhibits too broadly, it might be too immunocompromising.

Figure 1: Points where cell migration molecules operate during inflammatory responses.


Points 1–3 involve the multistep adhesion cascade of leukocyte binding to endothelium. Chemoattractants (green dots) signal chemoattractant GPCRs such as chemokine receptors or C5aR, leading to integrin activation and firm adhesion. Chemoattractants also attract leukocytes through tissues (point 4) and stimulate leukocytes to release inflammatory mediators such as histamine and proteases (point 5). An associated feature of many inflammatory responses is angiogenesis, in which chemokines are important (point 6). Finally, leukocyte egress from tissues, particularly lymphoid tissues, is regulated by S1P receptors (point 7), and stimulation of S1P receptors can limit the migration through blood and tissues by pathogenic T cells. At present, there are many drugs in preclinical and clinical development that target one or more of these points (Table 1). Selectin inhibitors operate at point 1; integrin inhibitors may operate at points 1, 3 and 4; chemoattractant receptor inhibitors operate at points 2, 4, 5 and 6; and S1P receptor–based drugs such as FTY-720 operate at point 7.

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Chemoattractant signaling is usually an essential event during the multistep process of leukocyte rolling and transendothelial migration. Consequently, inhibitors of many chemoattractants or their receptors have proven to be highly effective anti-inflammatory agents in a range of animal models of inflammation (see reviews by refs. 2, 3, 4, 5). However, inhibitors of the integrins and selectins have also proven to be highly effective in animal models of inflammation and in human disease. A second point at which a cell migration inhibitor may limit the inflammatory response is disruption of normal cell placement within a tissue. For instance, in human asthma, epithelial cell elaboration of eotaxins attracts eosinophils, which can subsequently damage airway epithelium6. CCR3 deficiency in mice does not prevent the binding of eosinophils to endothelium, but does result in their arrest in the subendothelial space and failure to traverse airway tissue7. Chemoattractants do much more than simply facilitate cell movement. The proinflammatory effects of chemokines or anaphylatoxins such as C5a derive from the release of inflammatory mediators by mast cells, macrophages and neutrophils, including substances such as histamine, myeloperoxidase and proteases (Fig. 1). Inflammatory responses often result in new blood vessel growth, and certain chemokines are important in stimulating vessel growth. Finally, chemoattractant receptors also regulate leukocyte retention within a tissue (Fig. 1). Manipulation of leukocyte retention by drugs such as FTY-720 is proving to be a successful approach for retaining T cells in lymphoid tissues, thereby limiting their migration to inflammatory lesions.

Some examples of the most advanced cell migration–based drugs in development (or approved) for inflammatory diseases are listed in Table 1. Drug developers now have a diverse range of candidate molecular targets to alter cell migration for the treatment of inflammation or cancer. Cell migration inhibitors can generally be divided into four classes. Three of these represent the three types of molecules involved in cell migration and adhesion: the selectins and their receptors, the chemoattractants and their receptors, and the integrins and their receptors (Fig. 1). A fourth class includes the signaling molecules downstream from adhesion or chemoattractant receptors, such as phosphoinositide-3-OH kinase- (PI(3)K-). The diversity of adhesion molecules and chemoattractant receptors, and their restriction to particular subsets of leukocytes, offers the possibility for selective inhibition of leukocytes—for instance, a leukocyte type implicated in the pathogenesis of disease. Various effector T cell subsets have been implicated in the pathogenesis of different autoimmune or allergic diseases. Likewise, mast cells, neutrophils and eosinophils, which tend to be considered in the context of innate immunity, can act as potent effector cells during inflammatory responses associated with adaptive immunity. The following sections outline many of the promising cell migration targets for subsets of T cells and other effector leukocytes.

Table 1: Promising targets and drug development programs for cell migration inhibitors



Full table

Selectin inhibitors
Leukocyte tethering and rolling, mediated usually by three selectins (L-selectin, P-selectin and E-selectin), are the first steps in the process of leukocyte binding to vascular endothelium (Fig. 1). L-selectin is involved in the homing of T cells to lymphoid tissues but is also expressed on other leukocyte types, where it participates in inflammation. E-selectin is expressed selectively on skin endothelium, whereas P-selectin is expressed on inflamed endothelium and by certain leukocytes. Expression of both E- and P-selectins is regulated by inflammatory stimuli. P-selectin glycoprotein ligand-1 (PSGL-1) is a mucin-like glycoprotein that binds P-selectin, as well as L- and E-selectin. It is expressed on certain leukocytes, as well as inflamed endothelial cells. Cutaneous lymphocyte-associated antigen (CLA) represents a modified form of PSGL-1 that interacts with E-selectin for skin homing by T cells.

Blockade of selectins or PSGL-1 inhibits several inflammatory conditions, at least in animal models. These will not be reviewed in detail here, as a recent review is available8. The most impressive experimental data are in models of ischemia-reperfusion, particularly in transplantation and myocardial reperfusion injury, and in atherosclerosis. One widely used selctin inhibitor is recombinant human PSGL-1-Ig fusion protein (rPSGL-1-Ig), whose mechanism of action is prevention of neutrophil entry to inflamed or reperfused tissues. However, results of human trials with selectin inhibitors have been mixed. The most promising selectin inhibitor in human trials appears to be Bimosiamose, which is a pan-selectin inhibitor developed by Revotar Biopharmaceuticals. It was effective in models of allograft and xenograft rejection and in mouse models of asthma. Revotar has reported positive results for human phase IIa clinical trials for chronic obstructive pulmonary disease (COPD), psoriasis and asthma (http://www.revotar.com).

Integrin inhibitors
Natalizumab, the mAb to 4 integrin developed by Biogen-Idec and Elan for the treatment of multiple sclerosis and Crohn's disease, together with another integrin inhibitor, efaluzimab (Raptiva), validates the effectiveness of migration inhibitors for human inflammatory diseases. Natalizumab binds to both 41 (VLA-4) and 47. Several studies in rodents indicated that an 4-integrin inhibitor should be highly effective for human multiple sclerosis and inflammatory bowel disease. The results of two phase 3 clinical trials showed that natalizumab markedly reduces the number of relapses in individuals with multiple sclerosis9. The notable adverse effect of these trials was the development in two subjects of progressive multifocal leukoencephalopathy, a condition caused by a polyoma virus, JC virus. This complication has resulted in restrictions on the type of patient that can receive the drug.

CD11a-CD18 (LFA-1) is one of the important integrins for leukocyte binding to endothelium and subsequent migration through tissue. Efaluzimab is a humanized mAb that was approved in 2003 for the treatment of moderate to severe plaque psoriasis. A recently published long-term study demonstrated sustained improvement in psoriasis symptoms in subjects throughout three years of continuous treatment10. Thus, efaluzimab is one of the most effective treatments for psoriasis at present.

In addition, other promising approaches in pharmacological targeting of integrins are being developed. The successful molecular modeling of integrins has allowed development of small molecule allosteric antagonists and ligand mimetics (reviewed in ref. 11). In addition, statin compounds, commonly used for the treatment of hypercholesterolemia, also selectively block LFA-1-mediated adhesion and costimulation of lymphocytes and suppress inflammation in a mouse model of peritonitis12. Nevertheless, use of statins as anti-inflammatory drugs in humans has not yet been reported.

Chemoattractant receptor inhibitors
Neutrophils, eosinophils and mast cells express many chemoattractant receptors that serve both innate-immunity and inflammatory functions. Excessive neutrophil influx has been implicated also in immune-mediated inflammatory disorders such as psoriasis, rheumatoid arthritis and inflammatory bowel disease, and, as previously mentioned, excessive eosinophil recruitment has been implicated in the pathogenesis of asthma. Discussed below are some of the most promising chemoattractant receptor targets for inflammatory reactions. Those receptors involved in T cell–mediated inflammatory diseases are discussed separately, although there can be considerable overlap in expression of receptors by macrophages, neutrophils and eosinophils, and by particular T cell subsets.

C5a receptors
The complement component C5a is one of the most potent chemoattractants for neutrophils and eosinophils. It also activates other leukocytes including mast cells and basophils. The detrimental effects of uncontrolled C5a production have been verified in many inflammatory conditions, particularly those involving the pathogenic effects of neutrophils. For instance, overproduced C5a or upregulated C5aR expression has been implicated in the pathogenesis of rheumatoid arthritis, respiratory distress syndrome, inflammatory bowel disease, systemic lupus erythematosus (SLE), ischemia-reperfusion injury, COPD and sepsis (reviewed by ref. 13). Mice genetically deficient in one of the receptors for C5a (C5aR) and antagonists that block binding of C5a to its receptor have established the validity of this receptor as a therapeutic target for many autoimmune diseases and acute inflammatory conditions13, 14. Genetic anomalies in regulators of the alternative pathway of complement, such as complement factor H, are associated with particular autoimmune diseases of the kidney and also of the eye, notably age-related macular degeneration15; such diseases represent attractive indications for C5aR antagonists. A second receptor exists for C5a, termed C5L2 (also called GPR77), but its precise function is uncertain. Although this receptor does not signal in the classical fashion like C5aR, it may serve a role in inflammation. Some studies have suggested that C5L2 acts as an anti-inflammatory molecule16, whereas other studies have suggested a proinflammatory role17. Recently, C5L2 deficiency and C5L2-specific antibodies have been shown to protect against sepsis induced in mice by cecal ligation and puncture18, although it still appears that C5aR, rather than C5L2, is overwhelmingly the important target.

Over the past decades, even before the discovery of C5aR, many research groups have tried to develop highly potent and specific small molecule antagonists to block C5a function. This approach has turned out to be surprisingly difficult, probably because C5a has a relatively high molecular weight (>10,000) and binds to C5aR through two or more sites. Novo Nordisk and G2 Therapies have developed a high-affinity mAb to human C5aR (ref. 19), which is now in early clinical trials.

The increasing ease of producing transgenic mice with humanized receptors or ligands will likely establish the ready use of 'human' knock-in mice for new drug development. Four humanized chemoattractant receptor knock-in mice have been reported so far, including C5aR (ref. 19) and also CXCR2 (ref. 20), CCR2 (ref. 21) and CCR5 (ref. 22). Human molecule knock-in mice are particularly useful for preclinical development of drugs that show selectivity for the human target. Many of the best antagonists that have come from initial screens are deprioritized because of their species selectivity. In studies with C5aR mAbs, we have successfully used human C5aR knock-in mice in an inflammatory model. Passively transferred inflammatory arthritis in K/BxN h.C5aR knock-in mice could be prevented or reversed with an mAb specific to human C5aR19 (Fig. 2). One problem with using human molecule knock-in mice is whether the mouse ligand (or receptor) binds with similar affinity and functionality as does the natural human ligand (or receptor); this is the case for the human C5aR and CXCR2 knock-in mice, and, fortunately, many mouse chemokines bind with similar fidelity to human receptor counterparts, although in some cases—for example, CCR2—they show decreased efficacy and potency.

Figure 2: An example of the use of a human-molecule knock-in mouse for drug discovery and validation.


The mouse C5aR coding region was replaced with the human C5aR sequence, to create human C5aR knock-in mice. Mouse neutrophils display high expression of human C5aR, assessed using a human C5aR-specific mAb (left). Human C5aR knock-in mice develop inflammatory arthritis in the K/BxN model (middle). Human C5aR knock-in mice treated with mAb to human C5aR are completely protected (right). These human C5aR knock-in mice have been instrumental for the development of Novo Nordisk's C5aR mAb inhibitor. From Lee et al.19.

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CXCR2 and CXCR1
CXCR2 (and its close relative CXCR1) are attractive targets for a range of inflammatory diseases as well as cancers. CXCR2 is the principal chemokine receptor expressed on neutrophils, and its expression extends to eosinophils, mast cells and a small subset of T cells. CXCR2 serves as a receptor for the CXC chemokines that contain the sequence Glu-Leu-Arg near the N terminus, so-called 'ELR' chemokines, namely CXCL8 (IL-8) and CXCL1 (Gro-). CXCR2 inhibitors are highly effective in animal models of inflammation including lipopolysaccharide-induced lung neutrophilia and arthritis23. A negative sentiment developed about CXCL8 and its receptors after the failure of trials of a mAb to CXCL8 (Abgenix ABX-IL8) in human COPD24 and psoriasis. However ABX-IL-8 may not recognize the immobilized, in vivo active form of CXCL8, which may be one reason for the lack of clinical efficacy. In addition, CXCL8 is not the only CXCR2 or CXCR1 ligand expressed by activated epithelium and endothelium in inflammatory conditions. Hence, inhibitors that target CXCR2, or both CXCR2 and CXCR1, should be much more effective, as these should block six or more ligands. Most drug development activity has focused on CXCR2 because it binds many more ligands than does CXCR1. Patients with COPD, acute respiratory distress syndrome, rheumatoid arthritis and psoriasis would likely benefit from treatment with a CXCR2–CXCR1 inhibitor. In each of these conditions, neutrophils seem to play a pathogenic role and CXCR2 (and/or CXCR1) and their ligands likely play an essential role in neutrophil recruitment. In human rheumatoid arthritis, angiogenesis is likely to contribute to disease pathogenesis and so the anti-angiogenic effects of a CXCR2 inhibitor, as discussed below, may contribute to therapeutic effectiveness. One issue to resolve is the relative importance of CXCR2 versus CXCR1 and versus C5aR. A number of CXCR2–CXCR1 antagonists are in human clinical trials, the most advanced being Schering-Plough's CXCR2 small molecule inhibitor SCH 527123, already in phase 2 trials for COPD and 'neutrophilic' asthma.

Other inflammatory chemoattractant receptors
A number of companies have programs centering on CCR2 antagonism. Incyte has a CCR2 antagonist, INCB3284, which is now in phase 2a clinical trials in patients with rheumatoid arthritis and type 2 diabetes. Merck has a drug, MK0812, in phase 2 trials in subjects with multiple sclerosis. Millennium Pharmaceuticals has a humanized mAb, MLN1202, that targets CCR2. This drug failed in a phase 2 trial for rheumatoid arthritis but is now in trials for multiple sclerosis and atherosclerosis. A mAb to CCL2, possibly the most important CCR2 chemokine ligand, also failed in clinical trials. ABN912 had no effect in rheumatoid arthritis because it dramatically increased the serum concentrations of CCL2 by serving as a blood depot of this chemokine rather than eliminating it25. This result indicates that careful selection of the most appropriate antibody isotypes, their half-lives with and without their target molecules and the mechanisms of elimination must be carefully considered when developing therapeutic antibodies targeting chemokines. A particular problem with CCR2 antagonism might be promotion of Alzheimer's disease. In the brain, microglia may be neuroprotective by phagocytosing amyloid- protein. In a mouse model of Alzheimer's disease, CCR2 deficiency accelerates early disease progression and results in premature death26. Also, mice deficient in CCR2 (or CCL2) develop cardinal features of age-related macular degeneration, possibly because of defective clearance of C5a and immunoglobulin G (ref. 27). Whether CCR2 antagonists will produce a similar effect will be an important issue. At present, animal data suggest that CCR2 antagonists should be most useful in atherosclerosis and multiple sclerosis28.

Other promising chemoattractant receptors that have been targeted with small molecule inhibitors include CCR1 and the leukotriene B4 (LTB4) receptor, BLT1. Studies with BLT1-deficient mice have validated this receptor, at least in mouse inflammation. Substantial protection from disease was observed in the K/BxN mouse model of inflammatory arthritis29 and, to a lesser degree, in allergic airway models. Nevertheless, the issue exists of how close the biology of the human system matches that of the mouse, since human clinical trials of a LTB4 receptor antagonist found that LTB4 was not a major contributor to the inflammatory process in human rheumatoid arthritis30. CCR1 is an inflammatory chemokine receptor expressed on monocytes, T cells and dendritic cells and interacts with several of the inflammatory chemokines. CCR1 was one of the first chemokine receptors to be identified and so attracted considerable attention from the pharmaceutical industry. Several studies have demonstrated the importance of CCR1 in mouse models of inflammation, particularly in models of rheumatoid arthritis and in experimental autoimmune encephalomyelitis (reviewed in ref. 31). In one human clinical trial, an orally administered CCR1 antagonist developed by Schering AG and Berlex Biosciences showed no effect over placebo in a 16-week randomized, double-blind trial in relapsing-remitting multiple sclerosis. CCR1 is an example of an important target looking for the right therapeutic indication, and several other CCR1 antagonists (by Pfizer, Millennium Pharmaceuticals and ChemoCentryx/GlaxoSmithKline) are in human clinical trials, for indications such as rheumatoid arthritis and transplant rejection.

Chemoattractant receptors for T cell subsets
A straightforward concept that has emerged over the years is that T cell subsets express cell migration molecules appropriate to their functional program. For instance, naive T cells require the special microenvironment of organized lymphoid tissues for their priming and express L-selectin and CCR7, which facilitate migration across high endothelial venules. Expression of various chemoattractant receptors is carefully regulated during T differentiation from naive T cells to functional subsets. As such, the chemoattractant receptors are proving to be reliable markers for functional subsets of effector and memory T cells. CXCR5 marks T follicular helper (TFH) cells that provide T cell help to B cells. CRTh2 and CCR3 mark TH2 T cells, and CCR6 preferentially marks TH-17 cells (Fig. 3). The reason for the association of different receptors with the various T cell subsets and functional programs is because certain subsets need to be in specific places and interact with different leukocyte subsets. This faithful association of receptor expression with functional programs offers opportunities to either block or subdue select arms of the T cell response, for instance, pathogenic TH-17 cells that might be driving an autoimmune disease. Despite the widespread use of chemokine receptors as either markers, or targets, for different types of immune responses, a few considerations must be remembered. None of the individual T cell chemoattractant receptors shown in Figure 3 is absolutely specific for any of the T cell subsets, as they are expressed by innate immune cells and also by many other cells types. One topic not discussed here is receptor expression by CD4+CD25+ regulatory T cells. Chemoattractant receptors place regulatory T cells in the correct locations to facilitate their function, and the main receptors they express are those that have also been implicated in inflammatory diseases: CCR2, CCR4, CCR5, CCR6 and CCR7 (ref. 32). The question of course is whether inhibitors of these receptors will disrupt normal endogenous immune regulatory mechanisms.

Figure 3: Chemoattractants, cytokines and leukocyte types for different types of immune responses.


(a) TH1 cells produce the cytokine IFN-, which stimulates cells to produce chemokines such as CXCL10, a CXCR3 ligand. TH1 cells preferentially express CXCR3 and CCR5, and associate with leukocyte types such as macrophages. GVHD, graft-versus-host disease. (b) TH2 responses typically involve the cytokines IL-4 and IL-13, which stimulate chemokines such as the eotaxins, which recruit CCR3-expressing leukocytes, particularly eosinophils. Another TH2 expressed chemoattractant receptor is CRTh2, which is also expressed by eosinophils. (c) TH-17 cells produce IL-17 isoforms, and these stimulate ELR chemokines such as CXCL8, which attracts neutrophils. The main TH-17 chemoattractant receptor is CCR6, which binds the chemokine CCL20; CCR4 also serves as a chemoattractant receptor. (d) T cell–B cell interactions occur mostly in B cell follicles and germinal centers, and CXCR5—binding the chemokine CXCL13—orchestrates germinal center interactions. The TFH cells that provide help to B cells express CXCR5 and the cytokine IL-21.

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TH1 receptors: CXCR3, CCR5
TH1 cells are important effector cells for antiviral responses and are the main cell type that produces interferon- (IFN-). Knowledge of the relative importance of TH1 cells versus TH-17 cells as effectors for human autoimmune diseases is still evolving, but virtually all T cells in the synovial fluid of humans with rheumatoid arthritis express CCR5 (ref. 33). Individuals homozygous for the CCR532 mutation do not express functional CCR5 and are generally protected from developing rheumatoid arthritis, suggesting that CCR5 is a promising target for treatment of rheumatoid arthritis34. CCR5 is the most important co-receptor for HIV entry, and several pharmaceutical companies have produced small molecule CCR5 inhibitors. Pfizer's maraviroc (Selzentry) holds considerable promise for certain inflammatory conditions, as well as for inhibiting HIV entry into CCR5+ cells. Why does HIV target CCR5? CCR5 facilitates effector T cell and dendritic cell migration to mucosal surfaces, where exposure to HIV mostly occurs. CCR5 marks TH1 T cells, which have an antiviral role, and so infection of CCR5+ TH1 cells may also subvert immune defenses. Regardless, the association of CCR5 with HIV infection has resulted in CCR5 antagonists being one of the first chemokine-based drugs to be approved, although not as yet for inflammatory conditions. Study of CCR532 homozygous individuals suggests that CCR5 antagonists may also be useful therapy for graft-versus-host disease and transplant rejection35, 36. One potential downside of a CCR5 inhibitor could be compromised antiviral immune defenses, because, in a study of human West Nile virus infection, CCR532 homozygosity was significantly associated with death37, and intact CCR5 is also critical for survival of mice infected with West Nile virus38. However, the approximately 1–2% of people of European ancestry lacking CCR5 seems to survive perfectly well, although other mechanisms may compensate for its absence.

The other main chemokine receptor that marks TH1 cells is CXCR3, although its expression is somewhat different in being expressed on a wider variety of T cells, including some TH-17 cells. However its connection to antiviral defense is strong, as its ligands CXCL10 (IP-10), CXCR9 (MIG) and CXCL11 (ITAC) are strongly induced by IFN-. Like CCR5, CXCR3 shows a notable expression on T cells associated with particular inflammatory conditions, including rheumatoid arthritis33. Animal model data using CXCR3-deficient mice or CXCR3 inhibitors point to the utility of CXCR3 inhibitors for treating organ transplant rejection and rheumatoid arthritis39. An interesting feature of CXCR3 is that it also serves as an endothelially expressed receptor that promotes angiostasis. Therefore, inhibition of CXCR3 may remove inhibitory signals for new blood vessel growth. One utility of a CXCR3 inhibitor could be promotion of allograft or xenograft acceptance, because inhibition of CXCR3 on T cells would limit T cell recruitment to an inflamed graft, and inhibition of the angiostatic function of CXCR3 would promote angiogenesis and new blood vessel formation in the organ graft. A CXCR3 small molecule inhibitor from Amgen/Tularik failed in a human clinical trial for psoriasis, and since then no companies have reported other clinical trials. A mAb to CXCL10 (MDX-1100, Medarex) is now in clinical trials for ulcerative colitis. CXCL10 (IP-10) is perhaps the most important of the three ligands of CXCR3, and the results of this trial should provide guidance for other drug development programs. Another approach is inhibition of the two TH1 receptors, CXCR3 and CCR5, using one drug. A small molecule antagonist termed TAK-779 blocks both CCR5 and CXCR3 in humans and rodents and inhibits the development of adjuvant-induced arthritis in rats.

TH2 receptors: CCR3, CRTh2
TH2 responses involve a different set of cytokines, such as interleukin (IL)-4 and IL-13, and these induce chemokines such as the eotaxins (CCL11, CCL24 and CCL26), which attract eosinophils by binding the chemokine receptor CCR3 (see Fig. 3). CCR3 is one of the promising targets for allergic diseases and notably asthma, in part because it functions not only for eosinophil responses, but also for basophils, mast cells and some TH2 T cells. CCR3 is the dominant functional chemokine receptor expressed by eosinophils40, which are strongly implicated in the pathogenesis of human asthma. CCL11 (eotaxin) is secreted by bronchial epithelial and endothelial cells and presumably attracts eosinophils to the lungs of allergic asthmatic patients. Eosinophils release toxic substances, such as major basic protein, designed for defense against large extracellular parasites. Indeed, asthmatic airways resemble a tissue that is mounting an antiparasite response, namely mucous production, smooth muscle contraction (for expulsion of parasites) and eosinophil recruitment.

CCR3 inhibitors, as well as CCR3-deficient mice, have provided validation of this target, particularly in mouse models of allergic airway inflammation7, 41, 42, 43. One would think that the substantial in vivo data on interactions between CCR3 and eotaxins and their overexpression in human asthma would have given rise to many more drug development programs. However the eosinophil fell out of favor with drug companies, partly because of an unsuccessful clinical trial of an IL-5 mAb. It now appears that anti–IL-5 therapy does not totally suppress eosinophil numbers in tissues because other cytokines such as GM-CSF can also contribute to eosinophilia, and neutrophils can also contribute to asthma pathogenesis. A central issue in allergic diseases, particularly human asthma, is defining what cell type is the most 'pathogenic'. If eosinophils are important, then CCR3 represents an ideal target. If allergic diseases are driven more by IL-13–expressing TH2 cells, then other targets may be preferable, because CCR3 is expressed only by a subset of TH2 cells and is dispensable for T cell–mediated allergic responses41. An alternative application for a CCR3 antagonist is eosinophilic esophagitis, a prevalent form of food allergy that causes distressing symptoms—heartburn, nausea and vomiting. A single-nucleotide polymorphism in the human CCL26 gene is associated with susceptibility to eosinophilic esophagitis, and CCR3-deficient mice are protected in an experimental model of eosinophilic esophagitis44. A number of potent CCR3 antagonists have been described, and some have entered human clinical trials45.

CRTh2 (chemoattractant receptor–homologous molecule expressed on TH2 cells) is a receptor for the prostaglandin PGD2. CRTh2 is restricted to allergic-type inflammatory cells, including TH2 cells, eosinophils and basophils, and seems to be a much more reliable TH2-expressed receptor than CCR3. Several biological and genetic studies point to CRTh2 as a highly attractive target for allergic diseases. For instance, potent and selective CRTh2 receptor antagonists significantly reduce airway inflammation in animal models of allergic asthma46, 47. A small molecule compound from the biotech company Oxagen, termed ODC9101, is now in phase 2a clinical trials, and intense interest is growing around this target.

TH-17 cells and CCR6 and CCR4
IL-17-producing CD4+ T cells (TH-17 cells) represent a distinct T helper cell lineage48 involved in the pathogenesis of various autoimmune diseases (Fig. 3). TH-17 cells express CCR6 and CCR4, and this combination of receptors distinguishes this subset49, although TH-17 cells probably also express CCR2 and CXCR3 but not CCR5 (ref. 50). Certain IL-17 isoforms act to recruit neutrophils to inflammatory sites. For instance, administration of IL-17A into the airways of mice induces a substantial increase in neutrophils associated with production of CXCL1 and CXCL2 (ref. 51). Several studies suggest CCR6 inhibition holds promise for treatment of TH-17–related inflammatory conditions, such as rheumatoid arthritis52, and multiple sclerosis (F. Sallusto, personal communication). Synoviocytes from arthritic joints of mice and humans produce large amounts of CCL20, a ligand for CCR6, and administering a blocking CCR6 mAb substantially inhibits arthritis in a mouse model52. However, T cells in human rheumatoid arthritis uniformly express CCR5 and CXCR3 (ref. 33), typical TH1 receptors, and so the precise pathogenic role of TH-17 cells versus TH1 cells and their chemokine receptor expression need to be clarified. Inhibition of CCR6 may be more feasible and effective, from a drug development perspective, than inhibiting the many IL-17 isoforms. CCR6 is potentially 'druggable' using organic small molecules, although this target has proven difficult in small molecule screens, and, as such, CCR6 may be a prime target for other inhibitory approaches, such as a blocking mAb.

TFH cells and CXCR5
T cells provide help to B cells within germinal centers. The principal molecules responsible for T and B cell colocalization within germinal centers include CXCR5 and its chemokine ligand CXCL13 (ref. 53). Mice that lack CXCR5 have severely disrupted lymphoid follicles and mount poor T-dependent antibody responses.

The relevance of TFH cells for human disease is that overactive TFH cells drive B cells to make autoantibodies53. A good example of this effect is the San Roque mouse, which develops an antibody-mediated autoimmune disease because of an induced mutation that impairs repression of ICOS expression54. TFH cells also produce CXCL13, which is involved in lymphoid tissue neogenesis and hence may be relevant to the pathogenesis of various chronic inflammatory autoimmune diseases. CXCR5 as a target has not attracted much attention from the pharmaceutical industry because of the limited data available so far on the suitability of CXCR5 inhibitors for antibody-mediated autoimmune diseases, such as SLE.

The promise of tissue-specific cell migration inhibitors
The division of much of the T cell immune system into gut-associated or skin-associated homing subsets represents one of the fundamental subdivisions of the immune system (see the review by Sigmundsdottir and Butcher55 in this issue). It also presents an opportunity for the design of tissue-selective inhibitors for inflammatory diseases. It is now widely accepted that naive T cells migrate randomly between blood and lymphoid tissues, whereas effector and memory T cells polarize to phenotypes associated either with gut or skin tropism56. This polarization relates to the site where a naive T cell was originally primed, whether gut-associated lymphoid tissues or skin-associated lymphoid tissues. These tropisms probably represent a means for rationalization of immunological resources in that antigen-specific effector T cells are directed back to sites where they are most likely to encounter the provocative pathogen. However, the very same tissue-selective effector T cells that mediate host defense, in the gut for instance, can also be associated with pathogenic inflammatory responses, such as celiac disease, Crohn's disease or ulcerative colitis.

One of the promising tissue-specific migration inhibitors in late-stage clinical trials in Crohn's disease is the CCR9 inhibitor CCX282 (Traficet-EN) from ChemoCentryx. CCR9+ T cells contribute to pathogenesis of inflammatory bowel disease in mouse models. The fundamental role of integrin 47 for gut homing by T cells and the success of an 41 mAb suggest that blockade of 47 should be effective for human inflammatory bowel disease. Studies in primates have shown that blockade of 47 with a mAb is highly effective for the treatment of colitis57. A recent clinical trial with a humanized mAb to 47 (MLN002) in patients with active ulcerative colitis demonstrated a superiority over placebo58. Drugs such as CCX282 or mAb to 47 may have fewer side effects, as they could avoid the broad immunosuppressive effects of current anti-inflammatory drugs and selectively target the pathogenic T cells associated with gut homing.

One of the chief defining molecules for T cell migration through the skin is CLA; this binds to E-selectin, which is preferentially expressed on inflamed endothelium in the skin. The chemokine CCL27 (CTACK) and its receptor CCR10 are key chemoattractant molecules for T cell migration to the skin, and neutralization of CCL27 suppresses skin inflammatory responses in animal models59. Inhibitors of CCR10 or CLA could be suitable for immune-mediated skin diseases, particularly psoriasis, although development of drugs has yet to be reported.

Blockade of lymphocyte egress: FTY-720
FTY-720 (Fingolimod) holds promise as a new blockbuster anti-inflammatory drug and, after natalizumab and efaluzimab, is the most advanced in human clinical trials. FTY-720 causes lymphocyte retention in lymph nodes, with a consequent lymphopenia in blood60. This drug is phosphorylated in vivo to yield a molecule that mimics sphingosine-1-phosphate (S1P) and acts as an agonist for four of the five members of the S1P family of GPCRs. The physiological role of S1P receptors on lymphocytes is to control their exit from lymphoid tissues61. This exit is very much an active and regulated process, and certain stimuli, particularly antigen challenge, can reduce lymphocyte exit from lymph nodes to almost zero, an effect described by sheep immunologists as 'lymphocyte shutdown'. FTY-720 sequesters lymphocytes in secondary lymphoid organs, thereby preventing their migration to sites of inflammation. This drug also limits T cell access to organ grafts and autoimmune lesions, reduces inflammation in many animal models and inhibits leukocyte recruitment in a mouse model of airway inflammation62. In an initial proof-of-concept study, FTY-720 reduced the number of MRI-measurable lesions and clinical disease activity in subjects with multiple sclerosis63. Sustained benefits after three years of treatment with the drug in subjects with multiple sclerosis were reported recently in an ongoing phase 2 study64. One potential side-effect of FTY-720 treatment is bradycardia due to expression of certain S1P receptors, particularly S1P3, in the heart. Hence, development of agonists that are selective for one particular receptor subtype, S1P1, are being pursued vigorously by several pharmaceutical companies.

Cell migration inhibitors, angiogenesis and cancer
The association of chemokines and chemokine receptors with angiogenesis, or with tumor cell metastasis, offers an opportunity for the development of new anticancer therapies. Chemokine signaling may act at many levels to promote tumorigenesis65. Certain chemokines mediate angiogenesis, thereby ensuring an adequate blood supply for tumor growth. Chemokines can also facilitate homing of endothelial progenitor cells to tumors, which promotes their growth66, 67, and deliver survival signals directly to cancer cells. Finally, expression of certain chemokine receptors, such as CXCR4 and CCR7, may promote tumor metastasis to lymph nodes or other tissues.

Molecules that regulate tumor-associated angiogenesis provide promising targets for treatment of cancers, as evidenced by the antiangiogenic drug bevacizumab (Avastin), an inhibitor of vascular endothelial growth factor. The ELR chemokines, such as CXCL8 and CXCL1, serve an angiogenic role through their binding to CXCR2 expressed by endothelial cells. ELR chemokines released by tumor cells induce microvascular endothelial cell migration and tube formation68. The other main chemokine receptors expressed by endothelium, particularly hypoxic endothelium, include CXCR4 and CXCR7. Expression of CXCR2 and CXCR4 and possibly CXCR7 is regulated by the transcription factor hypoxia inducible factor (HIF)69. This finding presumably relates to the connection between hypoxia and inflammation and the need to promote new blood vessel formation during an active inflammatory response. Several studies have shown substantial inhibition of tumor growth in animal models using chemokine or chemokine receptor inhibitors, particularly for CXCR2, CXCR4 and CXCR7 (refs. 70, 71, 72).

Tumor cells express various chemokines and chemokine receptors, some of which promote tumor growth and metastasis. For instance, CXCR3 is expressed on mouse and human mammary tumor cell lines. Antagonism of CXCR3 on breast tumor cells using a small molecule antagonist inhibits experimental lung metastasis73. CXCR7 is also selectively expressed by certain tumors71 and facilitates prostate cancer metastasis and progression74. Because expression of CXCR7 is restricted to many tumor types and to hypoxic endothelium, a mAb that effectively blocks CXCR7 function and kills CXCR7-expressing cells might be an ideal antitumor agent. Conceivably, CXCR7 may function by heterodimerizing with CXCR4 (ref. 75) and/or CXCR2. Although CXCR7 is a promising target for tumor therapy, the current availability of CXCR2 or CXCR4 small molecule antagonists makes a compelling case for a trial of these in selected human cancers. So far, few companies have revealed clinical programs for chemokine-based angiogenesis inhibitors. Chemokine Therapeutics Corp. has developed a peptide analog of the chemokine CXCL12, which antagonizes CXCR4, and it is in a phase 1/2 trial for cancer indications. A CXCR4 antagonist, AMD3100, has been shown to mobilize CD34+ stem cells from the bone marrow into the blood and augment migration of bone marrow–derived endothelial progenitor cells into sites of neovascularization after myocardial infarction. AMD3100 is being developed as a drug for mobilizing stem cells for transplantation in patients with multiple myeloma and non-Hodgkin's lymphoma. AMD3100 also decreases growth of both primary and metastatic breast cancer in mouse models76.

Targeting hints from viruses and human genetics
A growing number of virally encoded proteins subvert immune responses by binding to many different chemokines (reviewed in ref. 76). Indeed, the chemokine system is frequently targeted by pathogens to subvert immune responses, which suggests that pharmaceutical inhibition for human inflammatory diseases is also a worthwhile approach. Some viruses produce chemokine homologs, typified by vMIP-II, which shows broad antagonistic activity. Another strategy is the use of membrane-expressed chemokine receptor homologs, such as US28 of human cytomegalovirus, which sequesters chemokines to dampen host responses. Finally, some viruses simply use secreted chemokine-binding proteins, such as M-T7 of myxoma virus, that bind chemokines with high affinity. vMIP-II, encoded by Kaposi's sarcoma herpesvirus HHV8, antagonizes many of the TH1-associated receptors, such as CCR1, CCR2 and CCR5, but stimulates TH2-associated receptors such as CCR3. A noteworthy feature of most viral chemokines or chemokine-binding proteins is their broad chemokine or receptor-binding capabilities, which suggests that viruses need to circumvent chemokine redundancy for effective immune subversion (76).

Many polymorphisms have been identified in genes encoding cell migration molecules, particularly chemokines and their receptors. A number of these are associated with human inflammatory diseases or protection from disease. Several have been mentioned above and others are listed in Table 2. In general, the strong association of a gene polymorphism with human disease, such as CCR5 for rheumatoid arthritis, makes a compelling case for targeting a particular molecule. One pending opportunity is the incorporation of pharmacogenomic strategies into the clinical use of migration inhibitors. For example, it would make little sense to give a CCR532 individual a CCR5 inhibitor, whereas an individual with an allergic disease and a polymorphism in CCL26 might be an ideal patient for a CCR3 antagonist.

Table 2: Some important polymorphisms in human cell migration–related systems, and inflammatory disease associations



Full table

Lessons learned and future directions
Pharmaceutically, the preferred method of drug delivery is a pill taken orally. The chemoattractant receptors are GPCRs, which traditionally have been 'druggable' by organic small molecules, a reason why the pharmaceutical industry has embraced chemoattractant receptors so enthusiastically. However, drugs targeting chemoattractant receptors have had a slow genesis. The complement receptor C5aR was discovered 15 years ago, yet few small molecule inhibitors have been described. Likewise, chemokines and their receptors have also been known for some time, yet there is not a single chemokine receptor antagonist on the market for any indication other than HIV infection. The pitfalls in 'drugging' chemoattractant receptors should be fully appreciated, so that lessons can be learned and the full therapeutic potential of this system realized. First, there is still much to learn about the role of chemoattractants in human disease and how best to target cell migration molecules. We need to understand mechanistically how the activities of chemokines are regulated in vivo, the role of the non-signaling receptors such as CXCR7 and D6, and how important heteromerization of chemokines and their receptors is. An inhibitor of one receptor may cooperatively inhibit another receptor to which it heterodimerizes. CCR2 and CCR5 form heterodimers, as do CCR2 and CXCR4 (ref. 78). Thus, chemokine receptor antagonists may regulate allosterically the functional properties of receptors that they do not bind directly78. One of the other big problems is the difficulty in translating findings in the mouse to humans. Information gained from disease models—for example, knockout mice—does not necessarily reflect the human situation. Ultimately, the many human clinical trials of cell migration inhibitors (Table 1) will reveal the roles of the different selectins, integrins and chemoattractant receptors in human inflammatory diseases.

Original discovery efforts for organic small molecule inhibitors of chemoattractant receptors relied on competition ligand binding assays, because these were amenable to high-throughput assays. Experience now indicates that chemoattractant receptor inhibitors are best identified through functional assays such as calcium flux or chemotaxis. Many of these receptor inhibitors now in development are allosteric inhibitors and work by binding to a site other than the natural ligand binding site. A good example is the CCR5 inhibitor TAK779, which inhibits all of the ligands of CCR5 by binding to a site in the transmembrane spanning helices, remote from the ligand contact sites79. The deficiency of many of the early inhibitors, derived from competition binding assays, were that they often cross-reacted with one or more of the hundreds of different GPCRs or ion channels, which was usually discovered relatively late during development. The difficulties inherent in modeling GPCRs, because of their seven-transmembrane structure, resulted in little if any rational antagonist design. Finally, many of the chemoattractant receptor small molecule antagonists developed against human targets lacked adequate affinity or functionality against the homologous target in mice. In some cases, years of synthetic work were spent making human antagonists that would work on rodent receptors.

Because some chemoattractant receptors have proven intractable to inhibition by small molecules, inhibition by mAbs has been an alternative approach. A distinct advantage of mAbs is that they can be used to both inhibit functional activity and kill receptor positive cells through mechanisms such as antibody-dependent cell-mediated cytotoxicity. This latter feature may be advantageous for removing a pathogenic cell type expressing a particular target. For instance, plasmacytoid dendritic cells selectively express the chemoattractant receptor ChemR23 (ref. 80). Some of the best chemoattractant receptor candidates for blocking or killing using mAbs include CCR6 or CCR4 on TH-17 cells and CXCR5 on TFH cells and B cells. Kyowa Hakko and Amgen have developed a depleting mAb to CCR4 that is now in a phase 2 trial for psoriasis.

Truncated or otherwise modified chemokines such as Met-RANTES have been used extensively in animal models and demonstrate a substantial inhibition of inflammation (reviewed in ref. 5). There is one notable clinical program employing a modified chemokine, by Chemokine Therapeutics Corp, whose drug CTCE-9908 is a peptide analog of the chemokine CXCL12 (SDF-1) and an antagonist of its receptor CXCR4; it seems promising in a phase 1/2 trial for cancer. A cyclic peptide derived from the C terminus of C5a serves as a potent antagonist for C5aR (ref. 81), and a drug based on this approach, developed by Arana Therapeutics, is in human trials. Finally, chemokines themselves could serve as drugs, either to stimulate certain effects or to serve as natural antagonists. Ligands of the TH1 related receptor CXCR3 naturally antagonize CCR3, a receptor implicated in TH2 responses.

This review has concentrated on adhesion and chemoattractant receptors. An attractive alternative is inhibition of chemoattractant receptor signaling. This topic is covered in detail by Thelen and Stein82 in this issue. The most promising class of such signaling molecules is PI(3)Ks83. Mice lacking one of the four isoforms, PI(3)K, possess neutrophils and macrophages that show impaired activation through chemoattractant receptors and poor chemotactic responses84. These mice are also protected in various models of inflammation85, including inflammatory arthritis86 and glomerulonephritis87. Several drug companies have produced effective small molecule inhibitors of PI3K (reviewed in ref. 88). These agents inhibit the function of several different chemoattractant receptors simultaneously, thus circumventing the redundancy issue. PI3K signaling also operates for receptors other than chemoattractant receptors, which may offer advantages and drawbacks.

Conclusions
The many clinical trials with cell migration inhibitors that are ongoing or planned should provide considerable new insight into the pathogenesis of human diseases. The already extensive studies of cell migration inhibitors in rodent models of inflammation provide grounds for optimism for the many ongoing and upcoming human trials (Table 1). It will be important for pharmaceutical companies to report the failures, as well as the successes, so that a better understanding is gained of human disease pathogenesis. There will almost certainly be a need to reassess the current animal models of inflammation as the true nature of human inflammatory diseases unfolds.

The promise of cell migration inhibitors for the treatment of inflammatory diseases, and possibly cancers and infectious diseases, is immense. The results of many ongoing clinical trials should further validate the impact this new class of drugs will have on human health and herald a new era for anti-inflammatory therapies.



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Acknowledgments

I thank A. Rot, J.-C. Gutierrez Ramos and I. Mackay for helpful suggestions. Supported by the Australian National Health and Medical Research Council and the Cooperative Research Center for Asthma and Airways.

Competing interests statement: The author declares competing financial interests.
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