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

Abstract

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 γc 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). TCD4+ cells were isolated from 34 RA patients and 15 healthy control individuals and were evaluated after treatment with PF-06651600. 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)-γ, tumor necrosis factor (TNF)-α, 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 γt and the secretion of interferon (IFN)-γ and TNF-α 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. 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.