Human A2-CAR T Cells Reject HLA-A2+ Human Islets Transplanted Into Mice Without Inducing Graft-versus-host Disease

Abstract

Background.Type 1 diabetes is an autoimmune disease characterized by T-cell–mediated destruction of pancreatic beta-cells. Islet transplantation is an effective therapy, but its success is limited by islet quality and availability along with the need for immunosuppression. New approaches include the use of stem cell–derived insulin-producing cells and immunomodulatory therapies, but a limitation is the paucity of reproducible animal models in which interactions between human immune cells and insulin-producing cells can be studied without the complication of xenogeneic graft-versus-host disease (xGVHD).Methods.We expressed an HLA-A2-specific chimeric antigen receptor (A2-CAR) in human CD4+and CD8+T cells and tested their ability to reject HLA-A2+islets transplanted under the kidney capsule or anterior chamber of the eye of immunodeficient mice. T-cell engraftment, islet function, and xGVHD were assessed longitudinally.Results.The speed and consistency of A2-CAR T-cell–mediated islet rejection varied depending on the number of A2-CAR T cells and the absence/presence of coinjected peripheral blood mononuclear cells (PBMCs). When <3 million A2-CAR T cells were injected, coinjection of PBMCs accelerated islet rejection but also induced xGVHD. In the absence of PBMCs, injection of 3 million A2-CAR T cells caused synchronous rejection of A2+human islets within 1 wk and without xGVHD for 12 wk.Conclusions.Injection of A2-CAR T cells can be used to study rejection of human insulin–producing cells without the complication of xGVHD. The rapidity and synchrony of rejection will facilitate in vivo screening of new therapies designed to improve the success of islet-replacement therapies.