Dominant role of intercellular adhesion molecule-1 in the pathogenesis of autoimmune diabetes in non-obese diabetic mice.
Intercellular adhesion molecule (ICAM)-1 is involved in forming the immunological synapse. The contribution of ICAM-1 to immune responses is not critical because mice with a disrupted ICAM-1 gene do not have grossly abnormal immune reactivity. Here we report on the surprising finding that diabetes-prone NOD mice with a disrupted ICAM-1 gene (ICAM-1(-/-)) are completely protected from disease development. While 64% of ICAM-1(+/+) and 44% of ICAM-1(+/-) female NOD mice developed overt diabetes until 310 days old, no ICAM-1(-/-) NOD mice became hyperglycaemic. Histological examinations revealed minor infiltration around pancreatic islets of ICAM1(-/-) NOD mice. Administration of cyclophosphamide caused a progression to severe islet destruction in ICAM-1(+/+) NOD mice within 10 days. In contrast, ICAM-1(-/-) mice showed only mild insulitis. Furthermore, ICAM-1(+/+) NOD mice showed an increase of IFN-gamma, interleukin (IL)-12p40 and IL-12p35 pancreatic mRNA levels, leading to an increased ratio of IFN-gamma: IL-4 and IL-12p40: IL-12p35 expression. In contrast, ICAM-1(-/-) NOD mice did not upregulate IFN-gamma or IL-12p40 gene expression but maintained IL-4 and increased IL-12p35 gene expression. These results identify a dominant and non-redundant role of ICAM-1 in the development of autoimmune diabetes.
Martin
S
S
German Diabetes Centre, German Diabetes Research Institute at the Heinrich Heine University, Düsseldorf, Germany. martin@ddfi.uni-duesseldorf.de
van den Engel
N K
NK
Vinke
A
A
Heidenthal
E
E
Schulte
B
B
Kolb
H
H
D000818:Animals; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000517:prevention & control; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D018799:Intercellular Adhesion Molecule-1