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.
| Original language | English |
|---|---|
| Pages (from-to) | 7023-32 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 166 |
| Issue number | 12 |
| Publication status | Published - 2001 |
Keywords
- Administration, Oral
- Animals
- Apoptosis
- CD8-Positive T-Lymphocytes
- Cell Movement
- Cytotoxicity, Immunologic
- Diabetes Mellitus, Type 1
- Disease Models, Animal
- Doxycycline
- Gene Expression Regulation
- Incidence
- Insulin
- Islets of Langerhans
- Lymphocyte Count
- Lymphocytic Choriomeningitis
- Lymphocytic choriomeningitis virus
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Promoter Regions, Genetic
- Rats
- Time Factors
- Tumor Necrosis Factor-alpha
- Viral Load