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) 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.
Balasa
B
B
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
La Cava
A
A
Van Gunst
K
K
Mocnik
L
L
Balakrishna
D
D
Nguyen
N
N
Tucker
L
L
Sarvetnick
N
N
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000473:pathology; D007527:Isoenzymes / Q000276:immunology; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D019076:Transgenes / Q000276:immunology
D001324:Autoantigens; D007527:Isoenzymes; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2