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in Type 1 Diabetes: Islet-Specific Expression Abrogates the Ongoing Autoimmune Process When Induced Late but Not Early During Pathogenesis1
*
Departments of Neuropharmacology and Immunology, The Scripps Research Institute, La Jolla, CA 92037; and
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
We report here that islet-specific expression of TNF-
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- enhanced disease incidence when induced through an
islet-specific tetracycline-dependent promoter system early during
pathogenesis. Blockade of TNF- during this phase prevented diabetes
completely, suggesting its pathogenetic importance early in disease
development. In contrast, TNF- 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-. This observation has importance for understanding the complex
role of inflammatory cytokines in autoimmunity.
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