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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 γc cytokine receptors and T cell receptor signaling, the present study aimed at evaluating the impact of PF‐06651600 on the status...

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Published in:International journal of rheumatic diseases 2023-04, Vol.26 (4), p.740-750
Main Author: Mohammad, Talar Ahmad Merza
Format: Article
Language:English
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Summary: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 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). 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)‐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. 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.
ISSN:1756-1841
1756-185X
DOI:10.1111/1756-185X.14643