Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer

Abstract

Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the up-regulation of proinflammatory activity that leads to destruction of insulin-producing pancreatic β cells in type 1 diabetes. Th2-type cytokines, such as IL-10, have immune regulatory function. Administration of IL-10, or IL-10 gene transfer, prevents autoimmune diabetes in nonobese diabetic (NOD) mice. However, constant administration of purified rIL-10 is not practical for long-term therapy to prevent diabetes. In this study, we transferred the BCRF-1 gene, an open reading frame in the Epstein-Barr viral genome with remarkable homology to mouse IL-10 (viral IL-10 or vIL-10), by an adeno-associated viral (AAV) vector to NOD mice to attain sustained vIL-10 gene expression. Like endogenous mouse IL-10, vIL-10 has potent immunoregulatory and immunosuppressive functions, but can be specifically distinguished from endogenous mouse IL-10 for monitoring of the transgene expression. A single systemic administration of AAV vIL-10 significantly reduced insulitis and prevented diabetes development in NOD mice. This protective effect correlated with sustained transgene expression and protein production. Moreover, splenocytes from the treated mice blocked diabetes transfer to NOD recipients, suggesting that vIL-10 induces an active suppression of autoimmunity. This study provides evidence to support the possibility of using vIL-10 gene therapy to prevent type 1 diabetes.

Interleukin-10 polymorphisms in Spanish type 1 diabetes patients

“…[5][6][7] Supporting this imbalance between Th1 and Th2 responses as a causative agent of the proinflammatory activity that leads to type 1 diabetes (T1D) is the suppression of autoimmune diabetes by viral IL-10 gene transfer in NOD mice. 8,9 Autoimmune diabetes (T1D; 0.4% prevalence) in humans may as well be caused by disregulation of the immune system leading to hyporesponsiveness of regulatory Th2 cells and activation of effector Th1 cells.…”

Adeno-associated virus-mediated human IL-10 gene transfer suppresses the development of experimental autoimmune orchitis

“…13,24 The effects of IL-10 on autoimmune diseases using experimental models have been studied for years, but the results are somewhat confusing. In nonobese diabetic mice, IL-10 supplementation prevented autoimmune diabetes in some experimental protocols, 11,12 whereas augmented it in others. 25 Similarly, the results of a recent study by Kaneko et al 26 of IL-10 in EAO differ from our present results.…”

“…The fact that IL-10 is an immunoregulatory cytokine 10 with potential therapeutic value for organ-specific autoimmune inflammatory disease [11][12][13][14] strongly suggest that IL-10 has the potential to suppress autoimmune inflammation occurring in the testes.…”

Vectors for the treatment of autoimmune disease

“…in the same model was also effective, reducing insulitis and preventing diabetes development. 56,57 An elegant study performed in the rat STZ-induced model of diabetes used an rAAV encoding a single-chain insulin analogue expressed from the hepatocyte-specific L-type pyruvate kinase promoter. Following injection of 10 11 viral particles into the portal vein, blood glucose concentration gradually decreased until normoglycaemia was achieved after 1 week and was maintained for more than 8 months.…”