Several efforts are ongoing to use stem cell precursors to generate islet-like tissues suitable for transplantation in autoimmune Type 1 diabetic (T1D) recipients. During the development of T1D, autoimmune T cells are thought to mediate damage specifically to islet beta cells via T cell receptor:MHC-mediated interactions. As such, one strategy for developing stem cell derived islet- like tissue is to ablate donor-derived MHC expression to avoid autoimmune recognition. Since most current approaches utilize stem cells that are allogeneic to the subsequent recipient, we determined whether islet donor MHC expression was actually necessary for islet rejection in spontaneously diabetic NOD mice. Specifically, we tested the requirements for donor MHC on syngeneic (NOD) or allogeneic (C57Bl/6) islets in NOD recipients. We found that donor MHC class I expression on islets was indeed required for rapid rejection of syngeneic islets with the majority of NOD MHC class I-deficient islets (7/11) surviving >100 days in NOD recipients versus 0/17 for wild-type NOD islets. In striking contrast, MHC I-deficient (9/9), MHC-II deficient (5/5), or MHC-I/II-double deficient (12/12) C57Bl/6 islets were acutely rejected in NOD mice. Notably, MHC-I/II-double deficient C57Bl/6 islets were uniformly accepted in non-autoimmune prone allogeneic BALB/c or BALB-H-2^g7 recipients. Moreover, recipient CD4 T cells but not CD8 T cells were required for acute rejection of MHC-deficient C57Bl/6 islet allografts in NOD recipients. Taken together, results suggest that the recurrence of disease in islet autografts is qualitatively distinct from the response to allografts and that the later response can occur via a CD4 T cell-dependent and donor MHC-independent response. Thus, MHC-deficient allogeneic stem cell-derived islet-like tissue may still be vulnerable to recognition in the autoimmune recipient. Rather, results suggest that autologous stem cell-derived (e.g. from recipient iPS cells) modified to prevent MHC expression may be preferable for avoiding autoimmune recognition in Type 1 diabetic recipients.

CITATION INFORMATION: Gill R, Coulombe M, Kupfer T, Beard K, Burrack A. Islet Rejection in Autoimmune NOD Mouse Recipients: Implications for Stem Cell Therapies. Am J Transplant. 2017;17 (suppl 3).

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