The Role Of Tcell Mediated Responses

Human recipient T cells are activated by cells in allogafts through direct engagement of the T-cell receptor by MHC antigens expressed by donor professional antigen presenting cells (direct activation), or by graft-derived peptides expressed on autologous antigen presenting cells in the context of self MHC antigens (indirect activation). Early in vitro studies of discordant xenogeneic cellular interactions in mice suggested a strong dependence upon the indirect pathway of activation. Among the reasons proposed for failure of murine T cells to respond directly to stimulation by xenogeneic cells were species specificity of CD4-class II and CD8-class I interactions, lower precursor cell frequencies, incompatibilities in costimulatory receptor-ligand interactions, and defects in cytokine effects across species barriers. These in vitro studies helped formulate the hypothesis that cell mediated xenograft rejection might be weaker than allograft responses, and thus potentially easier to control. In addition, in vivo examination of disparate skin xenograft rejection suggested a critical role for the CD4+ T-cell population in development of an effective xenogeneic immune response.

Studies of xenogeneic mixed leukocyte cultures using the human anti-pig comination clearly indicate that porcine cells are able to directly elicit proliferation and IL-2 production by human T cells. Studies using highly purified T cells devoid of human APC indicate that direct activation of human responders occurs through recognition of MHC antigen on p orcine APC. Furthermore, experiments in which using purified subpopulations of human T cells have been evaluated show that CD4+ T cells proliferate, express IL-2 receptors, and produce IL-2 following stimulation with porcine APC. Blocking experiments with unprimed CD4+ T cells or CD4+ swine-specific T-cell clones have shown these cells to be SLA class II-restricted, indicating the human TCR can directly engage swine MHC antigens, and that the CD4-class II MHC interaction is functional in the pig-to-human species combination. Limiting dilution analysis has indicated the precursor

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