Friday, 20 June 2014

Mice are not men

Noster R, Riedel R, Mashreghi MF, Radbruch H, Harms L, Haftmann C, Chang HD, Radbruch A, Zielinski CE. IL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells. Sci Transl Med. 2014 Jun 18;6(241):241ra80

Although T helper 17 (TH17) cells have been acknowledged as crucial mediators of autoimmune tissue damage, the effector cytokines responsible for their pathogenicity still remain poorly defined, particularly in humans. In mouse models of autoimmunity, the pathogenicity of TH17 cells has recently been associated with their production of granulocyte-macrophage colony-stimulating factor (GM-CSF). We analyzed the regulation of GM-CSF expression by human TH cell subsets. Surprisingly, the induction of GM-CSF expression by human TH cells is constrained by the interleukin-23 (IL-23)/ROR-γt/TH17 cell axis but promoted by the IL-12/T-bet/TH1 cell axis. IL-2-mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naïve and memory TH cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF(+) TH cells that coexpress interferon-γ and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF-only-producing TH cells that did not express TH1, TH2, and TH17 signature cytokines or master transcription factors. Our findings demonstrate distinct and counterregulatory pathways for the generation of IL-17- and GM-CSF-producing cells and also suggest a pathogenic role for GM-CSF(+) T cells in the inflamed brain of multiple sclerosis (MS) patients. This provides not only a scientific rationale for depleting T cell-derived GM-CSF in MS patients but also multiple new molecular checkpoints for therapeutic GM-CSF suppression, which, unlike in mice, do not associate with the TH17 but instead with the TH1 axis.

I have not got time today to discuss the different STATS and T-bets, etc. but in brief this study says that humans do not behave exactly as mice in the way they use immune growth factors...but hey we knew this already. The TH1/TH2 pathway so distinct in our furry chums is very wooly in humans.  Will GM-CSF be targeted for MS, maybe..but the problem of targeting cytokines like GM-CSF is that they exist in balances and remove on part of the balance 

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