McGovern, J; (2012) The influence of biologic therapy on the capacity of regulatory T cells to restrain Th17 responses. Doctoral thesis , UCL (University College London).

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Abstract

The importance of IL-17 is underscored both by its resistance to control by regulatory T cells (Treg) and the propensity of Treg to produce this highly inflammatory cytokine. I addressed whether Th17 cells are inhibited by Treg from anti-TNF treated rheumatoid arthritis (RA) and psoriatic arthritis patients (PsA) and defined the underlying mechanisms. Th17 responses were inhibited by Treg isolated from RA patients responding to the anti-TNF antibody adalimumab, but not by Treg from healthy individuals or patients with active RA. Furthermore, in patients with RA, response to adalimumab therapy was associated with a reduction in RORC+ Th17 cells and an increase in FOXP3+ Treg lacking Helios and CD62L expression. These Treg suppressed Th17 cells through inhibition of monocyte-derived IL-6, but independently of IL-10 and TGF-ß, which mediated suppression of Th1 responses. Surprisingly, therapy with the anti-IL-6 receptor, tocilizumab, did not result in a reduction in RORC+ cells in RA patients. Rather, tocilizumab reduced T cell IL-21 production, which was associated with a diminished memory B cell population. The acquisition of IL-17 suppressor function by Treg was not observed in RA patients responding to etanercept, a modified TNF receptor, or in PsA patients treated with either adalimumab or etanercept. Moreover, response to therapy was not associated with an increase in Treg number in these patients. In RA patients treated with etanercept the inability of Treg to suppress Th17 responses was associated with high levels of IL-17 production and high levels of RORC+ Th17 cells ex vivo. In contrast, there was a reduction in IL-17 production and RORC+ Th17 cells ex vivo in PsA patients treated with both adalimumab and etanercept. Furthermore, depletion of Treg from PBMC showed that Treg from healthy controls, patients with active PsA and PsA patients responding to adalimumab can modulate the production of IL-22, a key cytokine in inflammatory skin disorders. However, PsA patients responding to etanercept have an impaired ability to regulate production of this cytokine. In conclusion, the induction of IL-17 suppressing Treg by anti-TNF is both therapy and disease specific. These data provides a rationale for the therapeutic benefit of switching between different anti-TNF agents. Furthermore, the induction of highly potent Treg may offer an explanation as to why patients treated with adalimumab have an increased risk of developing Mycobacterium tuberculosis (TB).

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