Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice.

Abstract

Sllmm~AFyThe T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Thl lymphocytes and macrophages (Mr The nonobese diabetic mouse strain (NOD/Shi) develops a Me and T cell-dependent autoimmune diabetes that closely resembles human insulindependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-IO positive I-A/3g 7/g7, I-E-mice in first (N2) and second (N3) generation backcrosses between IL-10 transgenic BALB/c mice and (NOD/Shi) mice. None of the IL-10 negative major histocompatibility complex-identical littermates were diabetic at this age. Furthermore, diabetes developed in 33% of I-A/3g TM, I-E + N3 mice in the presence of IL-10 before the mice were 10 wk old. Our findings support the notion that IL-10 should not simply be regarded as an immunoinhibitory cytokine, since it possesses powerful, immunostimulatory properties as well. Furthermore, our observations suggest that/3 cell destruction in NOD mice may be a Th2-mediated event.

Different Therapeutic Outcomes in Experimental Allergic Encephalomyelitis Dependant Upon the Mode of Delivery of IL-10: A Comparison of the Effects of Protein, Adenoviral or Retroviral IL-10 Delivery into the Central Nervous System

“…There was a significant increase in frequency of CD8 ϩ T cells and B cells in IL-10.tsF-treated mice. This supports previous work, which has shown that IL-10 can promote the growth of activated CD8 ϩ cells (38,39) and that increased pancreatic infiltration of CD4 ϩ , CD8 ϩ T and B cells were observed in an IL-10 transgenic model in NOD mice (40,41). In contrast to both the transgenic NOD study and the results we present here, transgenic mice constitutively producing human IL-10 (400 -700 pg/ml in serum) were protected from the induction of EAE and failed to show histological evidence of CNS infiltration (42).…”

The application of gene therapy in autoimmune diseases

“…In this study, the presence of the neomycin reporter gene in genomic DNA from recipient islets suggested that the transferred cells migrated to the pancreas and possibly proliferated in that area. Notably, this result stands in contrast to the results published by the same group, and another group, on transgenic expression of IL-10 in NOD mice, 31,32 illustrating the care needed in interpreting the implications of various models of potential immunotherapy.…”

Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses

“…21,37,38 However, these studies utilized cellular IL-10 which possesses immunostimulatory activities, including enhancing MHC class II expression and inducing cytotoxic T cell differentiation, that are not properties of vIL-10. In addition, recent studies have shown that both vIL-10-transduced islets and hepatic allografts produce biologically relevant amounts of vIL-10 that inhibit alloantigenic lymphocyte proliferation in vitro.…”

“…5,10,12 However, vIL-10 does not posses the T cell costimulatory activities of cellular IL-10. [20][21][22] Thus, the introduction of vIL-10 into allografts by direct gene transfer should reduce immunogenicity, impair effective antigen presentation, and suppress macrophage and T cell effector function, thereby inhibiting graft rejection.…”