A Mechanism for IL-10-Mediated Diabetes in the Nonobese Diabetic (NOD) Mouse: ICAM-1 Deficiency Blocks Accelerated Diabetes

Abstract

Neonatal islet-specific expression of IL-10 in nonobese diabetic (NOD) mice accelerates the onset of diabetes, whereas systemic treatment of young NOD mice with IL-10 prevents diabetes. The mechanism for acceleration of diabetes in IL-10-NOD mice is not known. Here we show, by adoptive transfers, that prediabetic or diabetic NOD splenocytes upon encountering IL-10 in the pancreatic 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-NOD.scid/scid mice elicited accelerated disease, demonstrating that pancreatic IL-10 but not endogenous IL-10 is sufficient for the acceleration of diabetes. Immunohistochemical analysis revealed hyperexpression of ICAM-1 on the vascular endothelium of IL-10-NOD mice. The finding suggests that IL-10 may promote diabetes via an ICAM-1-dependent pathway. We found that introduction of ICAM-1 deficiency into IL-10-NOD mice as well as into NOD mice prevented accelerated insulitis and diabetes. Failure to develop insulitis and diabetes was preceded by the absence of GAD65-specific T cell responses. The data suggest that ICAM-1 plays a role in the formation of the “immunological synapse”, thereby affecting the generation and/or expansion of islet-specific T cells. In addition, ICAM-1 also played a role in the effector phase of autoimmune diabetes because adoptive transfer of diabetogenic BDC2.5 T cells failed to elicit clinical disease in ICAM-1-deficient IL-10-NOD and NOD mice. These findings provide evidence that pancreatic IL-10 is sufficient to drive pathogenic autoimmune responses and accelerates diabetes via an ICAM-1-dependent pathway.

Intercellular Adhesion Molecule-1/LFA-1 Ligation Favors Human Th1 Development

“…For example, blocking Abs to LFA-1 and ICAM-1 were shown to prevent allograft rejection, associated with a shift from a Th1 to a Th2 cell cytokine profile (47)(48)(49). Similarly, ICAM-1 deficiency in nonobese diabetic mice blocked accelerated diabetes, in part explained by affecting the generation and/or expansion of islet-specific Th1 cells (50). Also, in an experimental autoimmune encephalomyelitis disease model, ICAM-1-deficient mice showed reduced T cell proliferation and reduced Th1 cytokine production in response to myelin Ag (51).…”

Dynamics of Pathogenic and Suppressor T Cells in Autoimmune Diabetes Development

“…Among the adhesion molecules involved in leukocyte trafficking into inflammatory sites and in the delivery of costimulatory signals during Ag presentation to T cells, CD54 appears to be critically important in the development of T1D. Administration of anti-CD54 mAb protects from disease (21,22), and a CD54-dependent pathway has been implicated in the pathogenesis of IL-10-mediated diabetes (23). In addition, NOD mice with a disrupted CD54 gene are completely protected from T1D (24), demonstrating the dominant and nonredundant role of this molecule in diabetes development.…”

Immunogenetics of Type 1 Diabetes

“…However, in the absence of ICAM-1, insulitis and diabetes could be prevented, thus providing evidence that IL-10 is sufficient to drive pathogenic autoimmune responses and accelerated diabetes via an ICAM-1 dependent pathway (Balasa et al, 2000). Presence of IL-10 during early stages of IDDM has also been shown to favor the generation of effector CD8 + T cells leading to accelerated diabetes in NOD mice (Balasa et al, 2000). Treatment of young mice with anti-TNF- and anti-IL-10 mAb has also been shown to prevent diabetes and insulitis (Lee et al, 1996, Yang et al, 1994.…”

“…In non-obese diabetic (NOD) mice (animal model for human Type 1 diabetes) pancreatic IL-10 has been shown to hyper-induce ICAM-1 expression on vascular endothelium. However, in the absence of ICAM-1, insulitis and diabetes could be prevented, thus providing evidence that IL-10 is sufficient to drive pathogenic autoimmune responses and accelerated diabetes via an ICAM-1 dependent pathway (Balasa et al, 2000). Presence of IL-10 during early stages of IDDM has also been shown to favor the generation of effector CD8 + T cells leading to accelerated diabetes in NOD mice (Balasa et al, 2000).…”