Open AccessA Dual Role for TNF-α in Type 1 Diabetes: Islet-Specific Expression Abrogates the Ongoing Autoimmune Process When Induced Late but Not Early During Pathogenesis
Author(s) -
Urs Christen,
Tom Wolfe,
Ursula Möhrle,
Anna Hughes,
Evelyn Rodrigo,
Elizabeth A. Green,
Richard A. Flavell,
Matthias G. von Herrath
Publication year - 2001
Publication title -
the journal of immunology/the journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.737
H-Index - 372
eISSN - 1550-6606
pISSN - 0022-1767
DOI - 10.4049/jimmunol.166.12.7023
Subject(s) - autoimmunity , immunology , pathogenesis , lymphocytic choriomeningitis , autoimmune disease , islet , tumor necrosis factor alpha , beta cell , type 1 diabetes , biology , immune tolerance , diabetes mellitus , immune system , cd8 , endocrinology , antibody
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.