The rejection of an organ graft continues to be the major problem in organ transplantation. The biological significance of alloreactivity itself is poorly understood. It has been suggested that alloreactivity may be a consequence of repeated environmental priming by microbial agents which may share antigenic determinants with major histocompatibility complex gene products. Clinical support for this hypotheses comes from the increased incidence of graft rejection seen in renal allograft recipients who develop cytomegalovirus infection after transplantation. Experiments in mice have shown the development of alloreactivity following Sendai virus infection, and enhanced levels of alloreactivity after murine cytomegalovirus infection. In this application, the investigators plan to study the development and specificity of alloreactivity in mice following infections with Sendai virus or cytomegalovirus. Differentiation will be made between the non-specific enhancement of immune function and specific alloreactivity by measuring the frequency of cytotoxic T lymphocyte (CTL) precursers and by the identification and cloning of CTLs with dual specificity for virus-infected host cells and allogeneic cells. Following the investigation of in vitro measures of alloreactivity, the effect of viral infection of allogeneic skin graft survival and vascularized cardiac graft will be evaluated. Mice specifically deficient in T cells or T cell subsets will be constructed to permit the study of the role of particular T cells in graft rejection, and the potential difference in T cells responsible for the rejection of skin vs. vascularized grafts. The effect of immunosuppressive therapy on the development of alloreactivity following viral infection will be explored. All previous work has evaluated unmodified hosts. By using immunosuppressive agents with known biologic actions, the mechanism of allogeneic cross-reactivity may be understood. Trials of immune globulin or cytomegalovirus vaccines are underway in humans. The studies proposed here may provide insight into the effect those regimens may have in humans transplantation.
