In autoimmune Type 1 diabetes (T1D), pancreatic islet allografts have somewhat limited long-term survival, both in T1D human subjects and in spontaneously diseased non-obese diabetic (NOD) mice. An ongoing issue centers on the nature of rejection of MHC-disparate grafts in T1D recipients. Therefore, the goal of this study was to determine whether or not islet allograft rejection was similar or distinct from the recurrence of autoimmunity that occurs in syngeneic islet grafts in the NOD mouse model of T1D. In particular we determined to role of islet donor MHC in islet rejection in NOD recipients. 500 syngeneic (NOD) or allogeneic (C57Bl/6; B6) islets were grafted in spontaneously diabetic female NOD mice. NOD islets were rejected in a mean of 13 days (n=15) while B6 islets vigorously rejected in a mean of 6 days (n=19), p<.01. Importantly, MHC class I-deficient (β2m-/-) NOD islets showed greatly prolonged survival with 7/11 NOD β2m-/- islet grafts surviving >100 days. MHC class II deficiency of NOD islets (class II-transactivator-/-) did not provide any additional survival of NOD islets. Moreover, the rejection of NOD β2m-/- islet grafts was significantly delayed in NOD mice following CD8 T cell depletion. Thus, disease recurrence in NOD islets appears to be a contact-dependent, CD8 T cell mediated process. However, the rejection of allogeneic B6 islets was strikingly distinct from this disease process. Neither MHC class I-deficient β2m-/- (n=6) nor MHC class II-deficient (I-Aβ-/-; n=5) B6 islets showed significant prolongation in diabetic NOD recipients. Furthermore, MHC I/II double-deficient B6 islets showed only modest prolongation with 6/6 grafts rejecting within 18 days. Importantly, 7/7 such MHC 'bald' B6 islet allografts survived indefinitely (>100 days) in non-autoimmune BALB/c recipients rendered diabetic with streptozotocin. Finally, rejection of MHC I/II double-deficient B6 islets was CD4 T cell-dependent but CD8 T cell-independent based on antibody depletion studies. Taken together, results indicate that islet allograft rejection in NOD mice invokes a particularly vigorous CD4 T cell response that does not require donor MHC expression, suggesting an 'indirect' form of donor antigen recognition. Thus, islet allograft rejection is both more rapid and is mechanistically distinct from conventional disease recurrence in vivo.

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