title: A dual role for TNF-alpha in type 1 diabetes: islet-specific expression abrogates the ongoing autoimmune process when induced late but not early during pathogenesis.
abstract: We report here that islet-specific expression of TNF-alpha can play a dual role in autoimmune diabetes, depending on its precise timing in relation to the ongoing autoimmune process. In a transgenic model (rat insulin promoter-lymphocytic choriomeningitis virus) of virally induced diabetes, TNF-alpha enhanced disease incidence when induced through an islet-specific tetracycline-dependent promoter system early during pathogenesis. Blockade of TNF-alpha during this phase prevented diabetes completely, suggesting its pathogenetic importance early in disease development. In contrast, TNF-alpha expression abrogated the autoimmune process when induced late, which was associated with a reduction of autoreactive CD8 lymphocytes in islets and their lytic activities. Thus, the fine-tuned kinetics of an autoreactive process undergo distinct stages that respond in a differential way to the presence of TNF-alpha. This observation has importance for understanding the complex role of inflammatory cytokines in autoimmunity.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: U
authors.initials: U
authors.lastname: Christen
authors.forename: T
authors.initials: T
authors.lastname: Wolfe
authors.forename: U
authors.initials: U
authors.lastname: Möhrle
authors.forename: A C
authors.initials: AC
authors.lastname: Hughes
authors.forename: E
authors.initials: E
authors.lastname: Rodrigo
authors.forename: E A
authors.initials: EA
authors.lastname: Green
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: M G
authors.initials: MG
authors.lastname: von Herrath
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000276:immunology; D015994:Incidence; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D051381:Rats; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D019562:Viral Load
chemical_list: D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D004318:Doxycycline