Wednesday May 03, 2023 - 11:00 to 12:35
Sarah J Colpitts, Canada has been granted the The American Association of Immunologists Awards
Cell therapy with group 2 and group 3 innate lymphoid cells prevents rejection in humanized models of islet transplant
Sarah J Colpitts1,2, Kyle T Reid1,2, Jessica A Mathews2, Vivian CW Fung3,4, C. Bruce Verchere3,4,5, Megan K Levings3,4,6, Sarah Q Crome1,2.
1Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada; 3Department of Surgery, University of British Columbia, Vancouver, BC, Canada; 4BC Children’s Hospital Research Institute, Vancouver, BC, Canada; 5Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; 6School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
Introduction: 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.
Methods: To assess the potential of harnessing human ILCs to improve islet transplantation, we examined the ability of ILCs to i) support the engraftment of islets and, ii) regulate harmful T cell subsets associated with the pathology of T1D. To assess whether ILCs were able to improve islet survival and engraftment, we performed in vitro co-cultures of allogeneic islets and ILCs and assessed the effects of ILCs on human islet engraftment and function following transplantation into streptozotocin-treated NOD-scidIL2Rgammanull (NSG) mice. To assess whether ILCs could prevent immune-mediated rejection of islets, we employed an antigen-specific model of islet transplant where HLA-A2+ islets are transplanted into NSG mice, and following engraftment HLA-A2-specific CAR T cells are transferred IV to induce islet rejection. The ability of adoptive cell therapy using ILC2s and ILC3s to prevent HLA-A2-specific CAR T cell-mediated rejection was assessed through blood glucose measurements. Additionally, the direct ability of ILC2 and ILC3s to regulate allogeneic T cell cytokine expression, expression of markers of inflammation, proliferation, and killing ability was assessed using in vitro suppression assays.
Results: In vitro and in vivo studies demonstrate ILC2s and ILC3s are not cytotoxic and do not negatively impact the engraftment of allogeneic human islets transplanted into NSG mice. Using an antigen-specific model of islet transplant rejection, we demonstrate the ability of ILCs to prevent CAR T-cell-mediated islet rejection. Cell therapy with both ILC2s and ILC3s suppress antigen-specific rejection by CAR T cells, resulting in sustained normal blood glucose levels. 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 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.
Conclusion: Collectively, these findings support that adoptive cell therapies with human ILC2s and ILC3s have potential in promoting tolerance in transplantation.
Canadian Institutes of Health Research (HH3-168005; PJT-165943). JDRF Canadian Clinical Trials Network (4-SRA-2020-953-A-N). QEII/Dr. Dina Gordon Malkin Graduate Scholarship in Science and Technology. Dr. Jesse Keshin Graduate Scholarship Award. Banting and Best Diabetes Centre Novo-Nordisk scholarship. SQC is supposed by a Tier 2 Canada Research Chair in Tissue-Specific Immune Tolerance, Canadian Foundation for Innovation (#38308) and the Medicine By Design Program (Canada First Research Excellence Fund). Thank you to the Ajmera Transplant Centre for supporting this work..