Use of allogeneic pMHCII-based 5MCAR-CTLs to eliminate alloreactive lymphocytes in transplant

PROJECT SUMMARY The immune system is a significant barrier to successful clinical organ transplantation, requiring life-long immunosuppression to prevent allograft rejection. Current immunosuppressive strategies rely primarily on broad pharmacologic inhibition of lymphocyte function. This approach is limited by susceptibility to breakthrough immune responses causing acute rejection episodes, with simultaneous unwanted impairment of protective immune responses against infection and tumors. Thus, new approaches for specific and durable allograft- specific immunosuppression are critically needed. We propose to utilize a pMHCII-based allogeneic 5-module chimeric antigen receptor-cytotoxic T cell (5MCAR-CTL) system to target and eliminate alloreactive CD4+ T cells. These investigations represent a conceptual advance in proposing to utilize cutting-edge cellular engineering with 5MCAR technology to develop a novel approach aimed at specific and durable immunosuppression in transplantation. Successful completion of the proposed experiments will generate tools and data to support refinement and development of this clinically-translatable cell engineering approach.