Background: Diabetes constitutes a significant problem in the transplant recipient. Diabetes is associated with impaired immunity to pathogens but its effect on alloimmunity remains ambiguous. Therefore, we sought to determine the impact of chronic hyperglycemia on allograft immunity.

Methods: C57Bl/6 (H-2^b) Ins2Akita mice (Akita) carry a mutated ins2 allele causing severe, chronic diabetes without autoimmunity. We used this model to assess the effect of chronic hyperglycemia on alloreactivity independent of autoimmunity. Alloreactivity was assessed by: 1) measuring cellular and humoral immunity after allogeneic spleen cell challenge and, 2) monitoring islet allograft rejection and tolerance. Akita mice or non-diabetic littermates were challenged with allogeneic BALB/c (H-2^d) spleen cells and the draining lymph node response was determined on day 5. Alloantibody responses were assessed by binding to H-2^d-expressing target cells day 7 after i.p. challenge with BALB/c spleen cells. In addition, allograft rejection was assessed in Akita or conventional streptozotocin (SZ)-induced diabetic recipients. Finally, the propensity for tolerance was assessed in Akita vs. SZ-induced recipients following anti-CD154 therapy.

Results: Chronic hyperglycemia had surprisingly little effect on primary T cell cycling (Ki67+) or cytokine (IFNγ) production following alloantigen challenge (n=8). However, BALB/c immunized Akita mice failed to produce detectable alloantibody (p<.01, n=4-5). Nevertheless, Akita mice vigorously rejected islet allografts relative to SZ-induced recipients (MST 9 vs 12 days). Finally, Akita mice resisted tolerance induction relative to SZ-diabetic recipients, even when supported with exogenous insulin (p<.01, n=9-13).

Conclusions: Despite impaired immunity to pathogens, chronic hyperglycemia does not compromise primary T cell responses and results in aggresive allograft rejection and a a surprising resistance to allograft tolerance. In contrast to primary T cell responses, alloantibody production is severely impaired in chronic hyperglycemia. Taken together, results illustrate the independent effects of chronic hyperglycemia on in vivo cellular and humoral alloresponses and identify chronic hyperglycemia as a novel barrier to tolerance induction.

CITATION INFORMATION: Bishop N, Beard K, Gill R. Distinct Effects of Chronic Hyperglycemia on Cellular and Humoral Alloresponses In Vivo. Am J Transplant. 2016;16 (suppl 3).

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