Springer Online Journal Archives 1860-2000
Conclusion The critical roles played by Fas/FasL and TNF/TNFR in AICD, peripheral T cell deletion and clonal downsizing have become increasingly apparent over the last few years. Consequently, new approaches have become possible for manipulation of T cell-mediated immune responses in either a positive or negative manner. For example, in disease states where excessive AICD involving FasL and TNF is observed there lies the possibility of intervention using specific inhibitors of these apoptotic pathways such as soluble forms of Fas and TNFR or neutralizing antibodies to TNF/TNFR or Fas/FasL interactions. Alternatively, the recent demonstration that the apoptotic pathways induced by FasL and TNF involve ICE-like caspases has revealed an opportunity to regulate apoptosis using inhibitors of this pathway. Indeed, in vivo treatment with a tripeptide inhibitor of ICE-like proteases (Z-VAD.fmk) protects mice from Fas-mediated hepatitis and death . Thus, a multi-faceted approach to the treatment of depletion of T cells arising from HIV infection may in the future include not only inhibitors of viral replication but also inhibitors of host cell apoptosis. In addition, treatment of tumors that express FasL may be aided by use of an inhibitor of Fas to allow generation of an anti-tumor T cell response or, alternatively, T cells reactive with the tumor may be expanded in vitro in the presence of Fas and TNF antagonists for use in adoptive immunotherapy. In the area of transplantation biology, transfection of the tissue to be transplanted with the gene for FasL may in some cases help prevent rejection of the graft by host T cells, although recent studies have indicated that so-called “immune privilege” does not result from simple expression of FasL. Moreover, the ability to induce selective elimination of antigen-reactive T cells by immunization in immune privileged sites (ACAID) may allow for induction of tolerance to antigens implicated in autoimmune disease. Finally, the recent demonstration that monocytes may be stimulated via CD4 cross-linking or treatment with M-CSF to induce AICD in T cells raises the possibility of loading these cells with antigen to induce tolerance by adoptive immunotherapy. Again, a strategy such as this might be used for the treatment of autoimmune disease or in the prevention of allograft rejection. On a cautionary note, however, it has become clear from recent studies that we are not in a position at present to manipulate T cell-mediated immune responses at will. Several studies in which the gene for FasL was transfected into cells to induce a state of “immune privilege” produced the opposite of the predicted effect. Further understanding of the apoptotic pathways that control the expansion and survival of T cells will undoubtedly allow the development of novel strategies for treatment of infectious disease, cancer, immunodeficiency and autoimmune disease.
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