Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice

Abstract

Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD × C57BL/6)F1 mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F1 mice shared the dendritic cell maturation defects and abnormal CD4+ T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.

IddLoci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

“…We have confirmed in this article that islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice (1). We now document that some but not all Idd resistance loci synergize with Idd3 to enhance islet allograft survival.…”

“…1,Idd5.2,and Idd5.3 (30). The Idd5.1 gene is most likely a variant of Ctla4, with the diabetes-prone NOD allele producing less of the ligand-independent CTLA-4 (liCTLA-4) molecule than the resistant B10 allele (38).…”

“…These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process. Diabetes 58: 165-173, 2009 T he NOD mouse is a model of type 1-like autoimmune diabetes and is used to study costimulation blockade-based transplantation tolerance within the context of autoimmunity (1)(2)(3)(4). However, costimulation blockade protocols fail in NOD mice.…”

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

“…NOD mice depleted of CD8 ϩ T-cells by antibody treatment do not develop diabetes (4), nor do CD8␣-deficient NOD mice (5). Similarly, diabetes does not occur in ␤2-microglobulin-deficient NOD mice, which lack class I MHC expression and therefore do not develop CD8…”

Islet Allograft Rejection in Nonobese Diabetic Mice Involves the Common γ-Chain and CD28/CD154-Dependent and -Independent Mechanisms

“…It is also believed that diabetic NOD mice may have developed an unusually large pool of memory effector T cells that can readily attack the islet transplants even before the activation of autoreactive and alloreactive T cells (3,4). Furthermore, certain evidence suggests that the NOD mice may have an inherent defect in the acquisition of peripheral tolerance (5)(6)(7). Clearly, such complexity is not equally represented in nonautoimmune mice, all of which may potentially contribute to the difficulty of islet transplantation in diabetic NOD hosts.…”