Pancreatic islet allografts are effective for restoring euglycemia in type 1 diabetics (T1D) but are vulnerable to rejection by autoreactive (islet-specific) and/or conventional alloreactive T cells. Since T1D recipients have a memory autoimmune response, autoreactive T cells are presumed to be responsible tolerance resistance found in the non-obese diabetic (NOD) mouse model of T1D. To test this concept, diabetic NOD mice with grafted with syngeneic (NOD.Rag^-/-) islets to model autoimmune disease recurrence or MHC mismatched (C57BL/6) islets to model islet allograft destruction. We determined whether CD4 or CD8 T cells were responsible for allograft tolerance resistance in NOD mice. Islet allograft recipients were treated with co-stimulation blockade therapy (anti-CD154 antibody) and / or LFA-1 blockade (anti-CD1a antibody) that individually promote tolerance in most non-autoimmune mouse strains. While one may expect that autoreactive CD4 T cells would be resistance to tolerance, analyzing islet graft-infiltrating T cells indicated that autoreactive (autoantigen tetramer expressing) T cells in NOD mice were markedly inhibited by CD154 blockade (but not by LFA-1 blockade). In contrast, presumptively alloreactive CD4⁺ T cells in NOD mice readily infiltrated islet allografts and this response was resistant to both therapies. To determine whether CD4⁺ T cell responses to MHC-derived or non-MHC-derived antigens drive allograft rejection, we transplanted diabetic NOD recipients with MHC-matched (B6.H-2^g7), minor antigen-matched (NOD.B10), or MHC class I and class II-deficient (B6.MHC-'bald') islets. Results demonstrated marked resistance to tolerance to all types of islet allografts relative to control NOD isografts following anti-CD154/anti-LFA-1 therapy (p < .05 for all groups relative to NOD islets). Moreover, this tolerance resistance was CD4 T cell dependent and CD8 T cell independent based on T cell depletion studies. Taken together, results indicate that despite the pre-existing host immunity to autoantigens, the allograft response that was actually more difficult to control than the autoimmune response alone. Thus, attempts to promote islet transplant tolerance in autoimmune recipients should take into account the strength of both autoreactive and especially alloreactive CD4⁺ T cell responses to major and/or minor histocompatibility antigens.

CITATION INFORMATION: Burrack A., Beard K., Coulombe M., Gill R. CD4⁺ T Cells Are Key Barriers to Tolerance Resistance to Islet Allografts in Autoimmune NOD Mice Am J Transplant. 2017;17 (suppl 3).

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