Tu230 - Adoptive Transfer of Group 2 and Group 3 Innate Lymphoid Cells Prevents Rejection in Humanized Models of Islet Transplant

Kyle Reid – Department of Immunology, Temerty Faculty of Medicine – University of Toronto; Jessica Mathews – University Health Network, Toronto – University Health Network; Vivian Fung – BC Children’s Hospital Research Institute; C. bruce Verchere, PhD – BC Children’s Hospital Research Institute; Megan Levings – BC Children’s Hospital Research Institute; Sarah Crome, PhD – Toronto General Hospital Research Institute, Ajmera Transplant Centre – University Health Network, Toronto

Abstract Text: Allogeneic islet transplantation is a potentially curative therapy for individuals with type-1 diabetes (T1D). However, it does not eliminate underlying autoimmunity, and individuals require life-long immunosuppression to prevent rejection. In murine studies, group 2 innate lymphoid cells (ILC2s) prevented islet rejection and group 3 ILCs (ILC3s) supported tolerance within islets, respectively. Here, we assess whether human ILC2s or ILC3s improve islet transplant in humanized models. In vitro and in vivo studies demonstrate ILC2s and ILC3s are not cytotoxic and do not negatively impact engraftment of allogeneic human islets transplanted in NOD-scidIL2Rgammanull(NSG) mice. Using an antigen-specific model of islet transplant rejection, where HLA-A2+ human islets are transplanted into NSG mice and following engraftment of islets, HLA-A2-specific CAR T cells with or without ILCs are transferred intravenously to induce rejection, we demonstrate the ability of ILCs to prevent CAR T-cell-mediated islet rejection. Both ILC2s and ILC3s suppress antigen-specific rejection by CAR T cells, resulting in sustained normal blood glucose levels when ILCs are present. In vitro studies revealed ILC2s suppress both autologous and allogeneic CD4+ and CD8+ T cell IFN-γ production and decrease expression of apoptosis-inducing molecule FasL on CD8+ T cells. ILC3s also display a moderate ability to inhibit allogeneic T cells in vitro, although not as efficiently as ILC2s, suggesting ILC3 effects in vivo may be via indirect T cell interactions. Collectively, these findings support that adoptive cell therapies with human ILC2s and ILC3s have potential in promoting tolerance in transplantation.