A mechanism for IL-10-mediated diabetes in the nonobese diabetic (NOD) mouse: ICAM-1 deficiency blocks accelerated diabetes

Neonatal islet-specific expression of IL-10 in nonobese diabetic (NOD) mire accelerates the onset of diabetes, whereas systemic treatment of young NOD mice with IL-10 prevents diabetes. The mechanism for acceleration of diabe tes in IL-10-NOD mice is not known, Here we show, by adoptive transfers, th at prediabetic or diabetic NOD splenocytes upon encountering IL-10 in the p ancreatic islets readily promoted diabetes. This outcome suggests that the compartment of exposure, not the timing, confers proinflammatory effects on this molecule. Moreover, injection of IL-10-deficient NOD splenocytes into transgenic IL-10-NODscid/scid mice elicited accelerated disease, demonstra ting that pancreatic IL-10 but not endogenous IL-10 is sufficient for the a cceleration of diabetes. Immunohistochemical analysis revealed hyperexpress ion of ICAM-1 on the vascular endothelium of IL-10-NOD mice, The finding su ggests that IL-10 may promote diabetes via an ICAM-dependent pathway, We fo und that introduction of ICAM-1 deficiency into IL-10-NOD mice as well as i nto NOD mice prevented accelerated insulitis and diabetes, Failure to devel op insulitis and diabetes was preceded by the absence of GAD65-specific T c ell responses. The data suggest that ICAM-1 plays a role in the formation o f the "immunological synapse", thereby affecting the generation and/or expa nsion of islet-specific T cells. in addition, ICAM-1 also played a role in the effector phase of autoimmune diabetes because adoptive transfer of diab etogenic BDC2.5 T cells failed to elicit clinical disease in ICAM-1-deficie nt IL-10-NOD and NOD mice. These findings provide evidence that pancreatic IL-10 is sufficient to drive pathogenic autoimmune responses and accelerate s diabetes via an ICAM-1-dependent pathway.