Efficacy of PF-06651600 in alleviating the pro-inflammatory capacity of CD4+ T cells in rheumatoid arthritis patients

Introduction PF-06651600 is a highly specific inhibitor of Janus-activated kinase 3 and the Tec family of kinases. Regarding its dual function in the inhibition of both gamma c cytokine receptors and T cell receptor signaling, the present study aimed at evaluating the impact of PF-06651600 on the status of T-helper cells (Th) as the central game players in the pathogenesis of rheumatoid arthritis (RA).Method TCD4(+) cells were isolated from 34 RA patients and 15 healthy control individuals and were evaluated after treatment with PF-06651600.Results RA patients had higher percentages of TCD4(+) cells, CD4(+) PD-1(+) cells, and CD4(+) PD-1(+) TIGIT(+) cells compared to a healthy control group and the TCD4(+) cells of these patients showed higher interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-17 secretion along with higher messenger RNA (mRNA) expressions of T-bet. The percentage of CD4(+) PD-1(+) TIGIT(+) cells showed a reverse correlation with the Disease Activity Score of 28 joints of the RA patients. PF-06651600 caused a significant decrease in the mRNA expressions of T-bet and RAR-related orphan receptor gamma t and the secretion of interferon (IFN)-gamma and TNF-alpha in TCD4(+) cells of RA patients. On the other hand, the population of CD4(+) PD-1(+) TIGIT(+) cells was expanded under the influence of PF-06651600. This treatment also reduced the proliferation of TCD4(+) cells.Conclusion PF-06651600 demonstrated a potential to modulate the activity of TCD4(+) cells in RA patients and to reduce the commitment of Th cells to the pathogenic Th1 and Th17 subsets. Further, it caused TCD4(+) cells to gain an exhausted phenotype which is associated with better prognosis in RA patients.