Tu141 - Alloantigen-specific CAR Tregs Protect Islets from Autoimmune Attack

Vivian Fung – University of British Columbia; Eleanor Chen – University of British Columbia; Majid Mojibian – University of British Columbia; Justin Spanier – University of Minnesota; Brian Fife – University of Minnesota; Megan Levings – University of British Columbia

Abstract Text: Type 1 Diabetes (T1D) is driven by T cells that kill beta cells in pancreatic islets. Islet transplantation is a therapeutic option; however, transplants are subject to attack by both alloimmune cells and pre-existing diabetogenic cells. We have previously shown that regulatory T cells (Tregs) engineered to express a chimeric antigen receptor that detects the alloantigen HLA-A2 (A2 CAR), suppress anti-HLA-A2 immunity in various pre-clinical models. However, the ability of A2 CAR Tregs to mediate bystander suppression of immunity targeting antigens distinct from HLA-A2 was unknown. We hypothesized that in the context of islet transplantation, A2 CAR Tregs may suppress killing of HLA-A2+ islets by islet autoantigen-specific T cells. To test this possibility, NSG mice were transplanted with islets from HLA-A2+ NOD mice and injected with diabetogenic (BDC2.5) CD4+ T cells (sorted Foxp3-negative) alone or with A2 CAR Tregs. Whereas BDC2.5 T cell-treated mice rapidly developed hyperglycemia, the majority of A2 CAR Treg-treated mice were protected. A2 CAR Tregs strongly engrafted in the mice and significantly reduced BDC2.5 T cell engraftment and proliferation in the blood and endogenous islets. In protected A2 CAR-Treg treated mice, the proportion of Foxp3-expressing BDC2.5 T cells progressively increased over time, suggestive of infectious tolerance. Remarkably, both the HLA-A2+ islet graft and HLA-A2-negative endogenous pancreas were protected in A2 CAR Treg-treated mice. These data show that A2 CAR Tregs mediate bystander suppression of autoreactive T cells in vivo and support the development of this approach to control allo- and autoimmunity in islet transplantation.