ALLOGRAFT RESPONSE TO LIVER TISSUE

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The current proposal represents a continuation of our investigation addressing the mechanisms of allograft rejection. We will concentrate on the ability of cellular components of the liver to stimulate an allograft response in order to better understand the mechanism(s) of liver allograft rejection and the potential for hepatocyte transplantation. These experiments will initially be undertaken in the murine models which have the benefit of l) well defined genetics 2) strong allograft responses 3) availability of immunodeficient animals 4) our familiarity with these models and techniques. Our ultimate goal, however, is to understand the mechanisms of human liver allograft rejection. To address the issue of the human response to alloantigen in vivo, investigators have had to study histology of grafts or to obtain cells or cytokines from peripheral blood or the local graft environment. The identification of recipient cells from the graft site requires in vitro growth and expansion of these cells. We feel the extension of our work into specific questions regarding the response of human cells to liver components requires the development of the SCID-hu model for transplantation studies. Tide development of a mouse reconstituted SCID (SCID-mu) is the logical first step in that process. The rationale for comparing the response of the SCID-mu to the intact host is that a) we can determine if the cellular response of the two are comparable in the face of rejection b) once we establish the cellular response seen in the SCID-mu as compared to the intact mouse we can omit cell populations considered nonessential for rejection in the reconstitution. This may help define cells that are essential for rejection c) similarly, differences in cytokine profiles in the face of rejection can help in the determination of essential cytokines for rejection. These areas will be the focus of future work. The SCID-hu and SCID-mu will enable us to study the host response to specific parenchymal cells in the absence of in vitro culture artifacts which has been shown to select for specific clones of donor reactive cells. Additionally, we hope to use the model to define the human response to human liver. These studies are designed to determine the local and systemic cellular and cytokin immune response to liver components. Furthermore, the trafficking patterns of immunocompetent cells in these models will be established. AIM I: Determine the influence of MHC antigen expression on in vitro and in vivo alloreactivity to components of the murine liver. AIM II: Development of the mouse reconstituted SCID model (SCID-mu) for transplantation studies. AIM III: Determine the murine cellular and cytokine response to cellular elements of the murine liver using the SCID- mu model as compared to the intact BALB/c host. AIM IV: Development of the SCID-hu model for transplantation studies. AIM V: Determine the human cellular and cytokine response to cellular elements of human liver.