Complexity of FasL-based immunomodulation. (A) Immunomodulation using noncleavable FasL expressed in target tissues or APCs. Noncleavable FasL is primarily apoptotic and effectively eliminates pathogenic T cells, resulting in the protection of target organs from autoimmunity and alloreactive immunity. (B) Wild-type FasL is cleaved from the surface of APCs or target tissues by matrix metalloproteinases (MMPs) and accumulates in intercellular space. sFasL blocks apoptosis by competing for Fas binding with the membranous FasL and serves as a chemotactic factor for neutrophils (C). (D) Destruction of target tissues expressing Fas. Cells in selected tissues, such as myocytes, express Fas and are sensitive to Fas/FasL-mediated apoptosis. Immunomodulation with APCs modified to express FasL or direct expression of FasL in such tissues results in tissue damage induced by the interaction of FasL with Fas.