RESUMO
The induction of antigen (Ag)-specific tolerance and replacement of islet ß-cells are major ongoing goals for the treatment of type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the NOD mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and the expansion of Foxp3+ regulatory T cells specific for the same Ag. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other ß-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with an HIP can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.
Assuntos
Diabetes Mellitus Tipo 1/terapia , Sobrevivência de Enxerto/efeitos dos fármacos , Insulina/administração & dosagem , Transplante das Ilhotas Pancreáticas/métodos , Fragmentos de Peptídeos/administração & dosagem , Animais , Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Feminino , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos NOD , Nanopartículas/administração & dosagem , RecidivaRESUMO
Diabetes is prevalent among solid organ transplant recipients and is universal among islet transplant recipients. Whereas diabetes is often considered to result in an immune-compromised state, the impact of chronic hyperglycemia on host alloimmunity is not clear. Potential immune-modifying effects of obesity, autoimmunity, or diabetogenic agents like streptozotocin may confound understanding alloimmunity in experimental models of diabetes. Therefore, we sought to determine the role of chronic hyperglycemia due to insulinopenia on alloimmunity using the nonautoimmune, spontaneously diabetic H-2b-expressing C57BL/6 Ins2Akita mice (Akita). Akita mice harbor a mutated Ins2 allele that dominantly suppresses insulin secretion, resulting in lifelong diabetes. We used BALB/c donors (H-2d) to assess alloimmunization and islet transplantation outcomes in Akita recipients. Surprisingly, chronic hyperglycemia had little effect on primary T-cell reactivity after alloimmunization. Moreover, Akita mice readily rejected islet allografts, and chronic hyperglycemia had no impact on the magnitude or quality of intragraft T-cell responses. In contrast, allospecific IgM and IgG were significantly decreased in Akita mice after alloimmunization. Thus, whereas diabetes influences host immune defense, hyperglycemia itself does not cause generalized alloimmune impairment. Our data suggest that immune compromise in diabetes due to hyperglycemia may not apply to cellular rejection of transplants.