EXCEED THE SPACE PROVIDED. A defect in Fas (Ipr mice) or FasL (gld mice) gene causes lupus-like autoimmune disease and accumulationof an abnormal DN T cell population bearing the TCR+CD4'CD8'B220+ surface phenotype. Activation-induced T cell death mediated by Fas/FasL, is a critical mechanism that contains autoreactive T cells and the DN T cells. Studies ofIl-2/Il- 2R gene knockout mice have revealed a correlation of an impaired FasL expression with autoimmune diseases. However, these mice do not accumulate the abnormal DN T cells and their autoimmune phenotype is different from Ipr and gld mice. We propose that IL-2 plays a dual role in the development of autoimmune disease. Initially IL-2 is required for the expansion of autoreactive T cells. Subsequently, IL-2 sensitizes activated T cells in such a way that a TCR re-ligationwill optimally activatefasl gene. FasL is produced to induce apoptosis of the activated T cells, including autoreactiveT cells. We propose thatfasl gene activation requires two signals sequentially deliveredthrough IL-2R and TCR. The cooperation between the two signals can be defined at the level of transcription factors that regulatefasl gene. We propose that the accumulation of autoreactive T cells and the abnormal DN T cells is dependent on IL-2. We have generated [II-2(-/-),fas(-/-)] mice. They do not develop /pr-like autoimmune disease and they do not accumulate the DN T cells. In addition, we propose that the abnormal DN T cells and autoreactive T cells in gld mice are sensitized to FasL and could be selectively eliminated by FasL. We have generated FasL-expressing bioactive vesicles (FasL VP), which displays potent FasL cytotoxicity and selectively kills the abnormal DN T cells. We have 3 specific aims. (1) Demonstrate a two-signal event for optimalfasl gene activation and define the specific and collaborative utilization of transcription.factors involved. (2) Determine how IL-2 regulates the developmentand deletion of the abnormal DN T cells and autoreactive T cells. (3) Demonstrate that FasL VP can delete both the DN T cells and the autoreactive T cells of gld mice and can be used to treat lupus erythematosus in animal models. PERFORMANCE SITE ========================================Section End===========================================
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