title: Overexpression of class I major histocompatibility complex accompanies insulitis in the non-obese diabetic mouse and is prevented by anti-interferon-gamma antibody.
abstract: Overexpression of class I major histocompatibility complex (MHC) proteins on pancreatic islet cells is a characteristic of autoimmune Type 1 (insulin-dependent) diabetes mellitus in humans and in animal models. Studies of post-mortem pancreases from humans with Type 1 diabetes suggest that overexpression of class I MHC proteins may precede mononuclear cell infiltration of the islets (insulitis). Pancreatic histology from the earliest stages of human Type 1 diabetes is rarely available. We have used the non-obese diabetic mouse, given cyclophosphamide to accelerate Beta-cell destruction, to investigate the temporal relationship between the overexpression of class I MHC protein and mRNA and other pathological changes associated with Beta-cell destruction. Prior to cyclophosphamide, immunoperoxidase staining showed that expression of class I MHC proteins was greater on islet cells and infiltrating inflammatory cells of the non-obese diabetic mouse than on islet cells of other mouse strains, whereas staining on exocrine cells was similar. On day three after cyclophosphamide administration, when insulitis had regressed, islet class I MHC protein expression had diminished. A dramatic increase in class I MHC protein expression occurred between days seven and nine, concomitant with reinfiltration of the islets by mononuclear cells; overexpression was seen both on islet cells and on surrounding exocrine cells, but only in the presence of mononuclear cell infiltration. By day 21, class I MHC protein overexpression was again confined to the islets, the exocrine pancreas being free of infiltration. Class I mRNA also increased dramatically by day eight but had virtually returned to normal by day 12.2+ effected by cytokines secreted by activated immuno-inflammatory cells. Class I MHC overexpression should enhance targeting of cytotoxic T cells to Beta cells bearing autoantigen.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: T W
authors.initials: TW
authors.lastname: Kay
authors.forename: I L
authors.initials: IL
authors.lastname: Campbell
authors.forename: L
authors.initials: L
authors.lastname: Oxbrow
authors.forename: L C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015152:Blotting, Northern; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000032:analysis* / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000032:analysis* / Q000235:genetics; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D010182:Pancreatic Diseases / Q000235:genetics / Q000276:immunology*; D011061:Poly A / Q000032:analysis / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D011061:Poly A; D012313:RNA; D007371:Interferon-gamma; D003520:Cyclophosphamide