Apoptosis of autoreactive CD8 lymphocytes as a potential mechanism for the abrogation of type 1 diabetes by islet-specific TNF-alpha expression at a time when the autoimmune process is already ongoing.
The role of TNF-alpha in type 1 diabetes pathogenesis is controversial. Using double transgenic mice expressing (i) the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) as an islet self-antigen and (ii) TNF-alpha under control of a tetracycline-regulated promotor system (tTA) in the pancreatic beta cells, we could previously demonstrate a differential effect of TNF-alpha on the incidence of type 1 diabetes. Most interestingly, late expression of TNF-alpha resulted in a reversion of mice that were already diabetic to a nondiabetic state. Here we provide a model of how experienced autoaggressive CD8 lymphocytes are dying by apoptosis as a result of beta cell-specific TNF-alpha expression at a time when the autoimmune process is already ongoing.
Christen
Urs
U
Departments of Neuropharmacology and Immunology, The Scripps Research Institute, La Jolla, California 92037, USA. christen@liai.org
Von Herrath
Matthias G
MG
D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D004318:Doxycycline