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Metabolic demand as an independent variable impacting tolerance induction to islet allografts

Ronald G. Gill¹, Mark Nicolls², Yonglie Ma³, Marilyne Coulombe¹

¹Surgery, University of Colorado, Denver, Aurora, CO; ²Medicine, Stanford University, Palo Alto, CA, United States; ³MMI, University of Alberta, Edmonton, AB, Canada

Background: There is a growing appreciation for the connection between metabolic demand/distress and intra-islet inflammation, especially as found in Type 2 diabetes. Importantly, inflammation can also impair allograft tolerance induction. Therefore, we determined if these concepts could be linked by determining whether severe hyperglycemia can impact the capacity to induce allograft tolerance in mouse models of diabetes.

Methods: We compared conventional streptozotocin (SZ)-induced diabetic mice with non-autoimmune, spontaneously diabetic Ins-2^akita(akita) recipients on the same C57Bl/6 (B6) genetic background for their relative propensity for induced islet allograft tolerance. BALB/c islets were transplanted in these recipients with or without transient treatment with anti-CD154 therapy (hamster MR1, days -1, 2, 7,9 relative to transplant).

Results: B6 akita mice have an insulin secretory defect that results in a severe, irreversible hyperglycemia that was consistently higher relative to corresponding SZ-induced diabetic B6 mice. Diabetic B6 akita mice accepted wild-type syngeneic B6 islet grafts for >100 days (12/12), confirming that diabetes was not associated with detectable autoimmunity. Unmodified islet allograft rejection was significantly faster (p< .01) in diabetic B6 akita hosts (7.1 days) relative to SZ-induced diabetic B6 mice (13 days). Importantly, anti-CD154 therapy resulted in graft prolongation but not long term allograft acceptance in the majority of diabetic B6 akita recipients (only 1/14 allografts surviving >100 days). This was significantly different from results using SZ-induced diabetic B6 recipients in which 8/12 allografts survived >100 days (p < .01).

Conclusions: Results indicate that there can be significant differences in islet allograft survival depending on the model of diabetes examined (SZ-induced versus akita). Given the higher and persistent hyperglycemia found in akita recipients, we hypothesize that the degree of metabolic demand and/or tissue distress in islet transplants can be an independent variable in determining islet graft survival and can inhibit tolerance induction.