Expression of intercellular adhesion molecule 1 on pancreatic beta-cells accelerates beta-cell destruction by cytotoxic T-cells in murine autoimmune diabetes.
Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by being involved in the extravasation of lymphocytes from the circulation into the inflamed pancreas. However, the mechanism of beta-cell destruction by which expression of ICAM-1 on beta-cells may facilitate adhesion of effector cells still remains to be elucidated. Several lines of evidence suggest that this adhesion molecule is involved in the destruction of pancreatic beta-cells by killer lymphocytes in the NOD mouse, which shows an autoimmune diabetic syndrome similar to that of human IDDM. Immunohistochemical study under light microscopy demonstrated that all of the mononuclear cells infiltrating the islets strongly expressed ICAM-1 and leukocyte function-associated antigen 1 (LFA-1), a counterreceptor of ICAM-1, whereas ICAM-1 expression on islet cells was not apparent. However, immunohistochemical staining under electron microscopy revealed that islet beta-cells adjacent to infiltrating lymphocytes were clearly stained by an anti-ICAM-1 monoclonal antibody (mAb). Flow cytometric analysis showed that the ICAM-1 expression on NOD islet cells and NOD-derived insulinoma cells (MIN6N8a) was inducible by interferon (IFN)-gamma or tumor necrosis factor-alpha. These cytokines had an additive effect on the ICAM-1 induction. Susceptibility of MIN6N8a cells to lysis by a NOD islet-derived CD8+ cytotoxic T-cell clone was greatly enhanced by IFN-gamma pretreatment, and this enhancement was abolished by anti-ICAM-1 and anti-LFA-1 mAbs. When both mAbs were administered into NOD mice with spontaneous or adoptively transferred diabetes, the development of diabetes was significantly prevented.(ABSTRACT TRUNCATED AT 250 WORDS)
Yagi
N
N
Second Department of Internal Medicine, Kobe University School of Medicine, Japan.
Yokono
K
K
Amano
K
K
Nagata
M
M
Tsukamoto
K
K
Hasegawa
Y
Y
Yoneda
R
R
Okamoto
N
N
Moriyama
H
H
Miki
M
M
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D007340:Insulinoma / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology / Q000648:ultrastructure; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016253:Microscopy, Immunoelectron; D010190:Pancreatic Neoplasms / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016169:Lymphocyte Function-Associated Antigen-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma