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.
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.
Christen
U
U
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Wolfe
T
T
Möhrle
U
U
Hughes
A C
AC
Rodrigo
E
E
Green
E A
EA
Flavell
R A
RA
von Herrath
M G
MG
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
D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D004318:Doxycycline