ITK inhibition promotes long-term survival of cardiac allografts by regulating T cell PLCγ phosphorylation.

Background: T cells express interleukin-2 inducible T-cell kinase (ITK), which is an essential modulator of T-cell signaling and function. However, the role of ITK in solid organ transplantation has not been investigated to date. Here, we studied the function of ITK in a murine cardiac transplantation model.

Method: Murine heart transplantation was performed using BALB/C mice as donors and C57BL/6 mice as recipients. Subsequent intraperitoneal injections of an ITK-specific inhibitor (BMS-509744) were performed to assess the effects of the kinase following cardiac transplantation. Additionally, naive T cells were isolated to investigate the inhibitor's potential effects in the alloimmune responses.

Results: ITK inhibition was found to promote long-term cardiac allograft survival compared with the control group of 36.0 ± 3.8 days vs. 7.0 ± 0.7 days, respectively ( < 0.01). While the Th1/Th17 percentages showed a decrease in prevalence ( < 0.001), the CD4CD25Foxp3 percentages were not markedly affected. treatment of CD4 T cells with the ITK inhibitor downregulated the proliferation, possibly by regulating the phosphorylation of PLCγ.

Conclusion: ITK inhibition resulted in lower Th1/Th17 responses after cardiac transplantation and markedly prolonged the mean survival time of the cardiac allografts. Thus, ITK inhibition might be a promising therapeutic target to alleviate alloimmune responses in the cardiac transplantation.