Enhanced cardiac allograft survival by Vav1-Rac signaling blockade in a mouse model.

Abstract Background Vav1-Rac signaling plays a pivotal role in TCR/antigen and CD28 signals for T cell activation. However, pharmacological interference of this signaling has not been tested in the prevention of alloimmune-mediated allograft rejection. It has been demonstrated that 6-thio-GTP, a metabolite of azathioprine, specifically inhibits Vav1-Rac activity in T lymphocytes. Here we show the immunosuppressive efficacy of 6-thio-GTP in the prevention of cardiac allograft rejection. Methods T cell proliferations were measured by 3 H-thymidine uptake. The immunosuppressive activities of 6-thio-GTP were tested in the cardiac allograft model of C57BL/6 (H-2 b ) to Balb/c (H-2 d ) mice. Results 6-Thio-GTP inhibited TCR/alloantigen stimulated T cell proliferation and CD28-dependent T cell survival. Administration of 6-thio-GTP (0.5 mg/kg) prolonged graft survival to 13.8 ± 2.39 days compared to 8.3 ± 0.48 days in PBS controls ( p p p  60 days) displayed reduced proliferative response to alloantigen and higher frequencies of regulatory T cells (Treg). Conclusion Vav1-Rac inhibitor 6-thio-GTP prolongs allograft survival alone or in combination with CsA by suppression of alloreactive T cell activation. Our findings suggest the therapeutic potential of pharmacological interference of Vav1-Rac signaling for transplantation.