| Research Abstract |
We have previously isolated thegenes encoding Fas and Fas ligand (FasL), and demonstrated that they are a receptor-ligand pair that mediates an apoptotic signal, and plays crucial rolesin the homeostasis of the immune system. Based on these findings, in this research, we have explored physiological and pathological roles of the Fas-FasL system. We have obtained the following results.
1. We have established (1) the production and purification procedure for the recombinant human soluble FasL,(2) mouse transfectants expressing high levels of cell surface FasL,(3) polyclonal and monoclonal antibodies against human or mouse FasL.
2. Fas expresses at high levels in the spleen germinal centers. In addition, LPS stimulation sensitize B cells to FasL.These results suggested a role of FasL in the apoptotic death of activated B cells.
3. Frashly isolated peripheral T cells from mice, which have been shown to resistant to agonistic anti-Fas antibodies, are actually susceptible to FasL-mediated apoptosis. We also discovered that T cell receptor engagement of fresh T cells induces resistance against FasL.These findings are very important to understand the regulatory mechanisms of T cell death by the Fas-FasL system.
4. A.highly sensitive ELASA system for human Fas ligand was established. Using this system, FasL were detected in sera from patients of LGL lekemia and NK lymphoma.
5. In vivo toxicity of human FasL was tested in mice. When 500 mug of FasL was intravenously injected, all mice were killed by sever hepatic failure. When mice were pretreated with propionibacterium acnes, ED_<50> of FasL was reduced to 50 times-less.
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