Significant progress has been achieved in elucidation of the immunologic mechanisms mediating rejection of human liver allografts; however, further progress is impeded by difficulty in obtaining adequate tissue for evaluation without subjecting the recipient to excessive risk. Thus, studies have been limited to histologic evaluation of liver biopsy specimens or cellular and cytokine profiles obtained from in vitro antigen-stimulation of peripheral blood lymphocytes or """"""""local environment"""""""" lymphocytes harvested from transplant recipients. While in vitro analysis has formed the foundation for our understanding of human rejection, it must be recognized that selection of reactive cell clones for study introduces significant culture artifact. Our goal is to evaluate the mechanisms responsible for human allograft rejection, in vivo, through development of a human-reconstituted, severe combined immunodeficiency mouse (SCID-hu) transplantation model. This model will facilitate performance of experiments designed to: 1) elicit specific cytokine profiles underlying human tissue rejection, 2) identify and characterize the function of specific human cell subsets mediating rejection, 3) identify the immunogenicity of specific human liver components, and 4) evaluate cellular or cytokine manipulations on transplant outcomes. This model can be expanded to assess the probability and mechanism of rejection in specific transplant patient- donor pairs. While the SCID-hu model has been extensively used in the evaluation of B-lymphocyte function, HIV pathogenesis, and autoimmune disease processes, a reproducible transplant model has not been established. Therefore, initial efforts will focus on refinement of a murine-reconstituted (SCID-mu) transplant model. The advantages conferred by a murine model of well defined genetics and predictable allograft responses will facilitate evaluation of the accuracy of the SCID transplant model and interpretation of human tissue results.
