Reciprocal role of cyclins and cyclin kinase inhibitor p21WAF1/CIP1 on lymphocyte proliferation, allo-immune activation and inflammation

We performed in vitro and in vivo studies using lymphocytes, and rat heart transplant model to understand the role of cyclins and p21 on mitogen and allo-induced lymphocyte activation and inflammation. Lymphocyte proliferation was studied by 3H-thymidine uptake assay and mRNA expression was studied RT-PCR.Activation of allo- and mitogen stimulated lymphocytes resulted in increased expression of cyclins, IL-2 and pro-inflammatory cytokines, which was inhibited by cyclosporine. The over-expression of p21 prolonged graft survival in a completely mismatched rat heart transplant model resulted by inhibiting circulating and intra-graft expression of proinflammatory cytokines.Cyclins play a significant role in transplant-induced immune activation and p21 over-expression has potential to inhibit T cell activation and inflammation. The results from this study will permit the design of alternate strategies by controlling cell cycle progression to achieve immunosuppression in transplantation.Alloimmune activation, caused by aberrant T lymphocyte proliferation is one of the key post transplant events in organ transplant recipients. Current immunosuppressive drugs are therefore designed to inhibit T lymphocyte proliferation. Our previous studies have demonstrated that immunosuppressive drugs, cyclosporine (CsA) tacrolimus (TAC), and sirolimus (SRL) besides inhibiting lymphocyte proliferation and IL-2 also induce the expression of TGF-β and other fibrogenic molecules [1-3] leading to nephrotoxicity and chronic rejection. Therefore, there is a need to develop alternate strategies to achieve immunosuppression for increased graft survival with least nephrotoxicity. The most effective immunosuppression can be achieved by the direct inhibition of T lymphocyte proliferation. Since the expression of cyclins and cyclin-dependent kinases and pro-inflammatory cytokines is increased during T lymphocyte proliferation (4), control of T cell proliferation by regulating the expression of cyclin