Differential expression of ICAM-1 and LFA-1 versus L-selectin and VCAM-1 in autoimmune insulitis of NOD mice and association with both Th1- and Th2-type infiltrates.
The infiltration of pancreatic islets by mononuclear cells is the hallmark of the development of insulin dependent diabetes mellitus (IDDM) in the NOD mouse, an animal model for human IDDM. The aim, of this study was to correlate adhesion molecule expression with the degree of islet infiltration and to compare Th1- and Th2-driven islet inflammation. Cryostat sections of NOD mouse pancreata before and after diabetes development were analysed by semiquantitative immunohistochemistry. NOD mouse islets did not show the expression of ICAM-1, LFA-1, L-selectin and VCAM-1 prior to infiltration by mononuclear cells. Furthermore, islets with early stage insulitis (grade 1, periinsular location of small infiltrates) still were devoid of adhesion molecule expression. ICAM-1 and LFA-1 were first demonstrable in islets with strong periinsular infiltrates (insulitis grade 2) while L-selectin and VCAM-1 were only seen in islets with mild or strong intraislet infiltration (grade 3-4). Adhesion molecules were demonstrable in areas of macrophage and T-lymphocyte infiltrates but not in adjacent endocrine islet tissue. Islets of all infiltration stages contained Th2 lymphocytes (positive for IL-4). Substantial numbers of Th1 cells (positive for IFN-gamma, TNF-alpha, IL-2 and/or IL-2 receptor) were observed only after acceleration of diabetes development by a single injection of cyclophosphamide (250 mg/kg i.p.). Interestingly, the adhesion molecule expression pattern in islets with "Th1' versus "Th2 insulitis' was not different. In conclusion, the expression of adhesion molecules in islets during the development of autoimmune diabetes does not precede mononuclear infiltration but probably occurs in response to the activation of initial small infiltrates. ICAM-1 and LFA-1 expression is seen prior to L-selectin and VCAM-1. However, adhesion molecule expression during Th1 versus Th2 cell infiltration is very similar, suggesting similar adhesion molecule requirements of the two Th subsets.
Martin
S
S
Diabetes Research Institute, Heinrich-Heine-University, Düsseldorf, Germany.
Hibino
T
T
Faust
A
A
Kleemann
R
R
Kolb
H
H
D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis*; D007515:Islets of Langerhans / Q000473:pathology*; D019041:L-Selectin / Q000032:analysis*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis*; D051379:Mice; D016688:Mice, Inbred NOD; D018417:Th1 Cells / Q000473:pathology*; D018418:Th2 Cells / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis*
D016169:Lymphocyte Function-Associated Antigen-1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D003520:Cyclophosphamide