*Purpose: Stem cell technology is an attractive approach for generating insulin-producing cells for transplantation in insulin-dependent diabetes and potentially can be genetically modified. One recent strategy is to eliminate donor MHC expression to avoid direct host T cell recognition of the donor. In this study we set out to determine whether MHC deficiency prevented islet allograft rejection in spontaneously autoimmune non-obese diabetic (NOD) mice.

*Methods: Diabetic female NOD mice were grafted beneath the left renal capsule with islets from the following types of islet donors: 1) NOD scid donors (H-2g7), 2) NOD donors deficient in both MHC class I (beta 2m^-/-) and class II (C2Ta^-/-), 3) wild-type C57Bl/6 (B6; H-2^d), and 4) B6 donors deficient in both MHC class I and class II (I-A^b-/-). After restoration of euglycemia, rejection was defined as the first of consecutive hyperglycemic readings. In the event of graft rejection, islet grafts were explanted and graft infiltrating cells (GIC) were cultured in 1L-15-containing media for three days and then antigen-stimulated to determine antigen specificity by ELISA (IFNg production).

*Results: Syngeneic NOD islets rejected in 12/12 recipients (MTR of 12 days). Rejection was greatly dependent on NOD MHC expression; 9/12 MHC-deficient NOD islets survived more than 100 days. B6 islet allografts showed accelerated rejection; 14/14 B6 islet grafts rejected in less than 10 days. Interestingly, B6 MHC deficient islets also rejected in NOD recipients with 15/15 MHC-deficient B6islet rejecting in less than 20 days. B6 MHC deficient islets survived indefinitely in non-autoimmune-prone BALB/c recipients (greater than 100 days) indicating that MHC was required for conventional islet allograft rejection. Interestingly, GIC from rejecting B6 MHC-deficient demonstrated pronounced alloreactivity (IFNg production) to B6 MHC-deficient splenic stimulator cells. This alloreactivity required the presence of NOD APCs, suggesting ‘indirect’ (host APC-dependent) recognition. GIC from rejecting NOD islet grafts did not demonstrate reactivity to either B6 or B6 MHC-deficient splenic APCs, indicating that reactivity was specific to the islet donor.

*Conclusions: While both disease recurrence and alloimmunity require islet MHC expression, islet allograft rejection in autoimmune recipients is donor MHC independent. We posit that underlying autoimmunity initiates an especially vigorous ‘indirect’ T cell alloresponse. As such, results suggest that abrogating donor MHC from allogeneic surrogate beta cell sources may not be sufficient to prevent rejection in autoimmune recipients. Rather, findings suggest that modified autologous stem cell sources may be effective at preventing islet rejection in the setting of autoimmunity.

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