ALLOGRAFT RESPONSE TO LIVER TISSUE

目前的提议代表了我们调查的继续 解决同种异体移植排斥的机制。我们将集中于 肝细胞成分刺激同种异体移植物的能力 反应，以便更好地了解肝移植的机制 排斥反应和肝细胞移植的潜力。这些 实验最初将在鼠模型中进行， l）明确的遗传学2）强同种异体移植反应3） 免疫缺陷动物的可用性4）我们对这些 模型和技术。然而，我们的最终目标是了解 人肝移植排斥反应的机制。为了解决 人类对同种异体抗原的体内反应，研究人员不得不研究 移植物的组织学或从外周血中获得细胞或细胞因子 或当地的移植环境。受体细胞的鉴定 移植部位需要这些细胞的体外生长和扩增。我们 我感到我们的工作扩展到具体问题， 人类细胞对肝脏成分的反应需要发展 用于移植研究的SCID-hu模型。小鼠的潮汐发育 重建的SCID（SCID-mu）是该过程中合乎逻辑的第一步。 比较SCID-mu与完整宿主反应的原理 a）我们可以确定两者的细胞反应是否 B）一旦我们建立了细胞模型， 与完整小鼠相比，我们可以忽略SCID-mu中观察到的反应 细胞群被认为是排斥反应的非必需的， 重组这可能有助于定义细胞， c）类似地，面对排斥反应时细胞因子谱的差异 排斥反应可以帮助确定必需的细胞因子， 排斥反应这些领域将是今后工作的重点。SCID-hu和 SCID-mu将使我们能够研究宿主对特定实质细胞的反应， 在没有体外培养人工制品的情况下， 选择供体反应性细胞的特定克隆。此外，我们希望 使用该模型来定义人体对人体肝脏的反应。这些 研究的目的是确定局部和全身的细胞和 细胞因子免疫反应肝成分。此外，贩运 将建立这些模型中免疫活性细胞的模式。 目的I：确定MHC抗原表达对体外和体外培养的人肝癌细胞的影响， 对鼠肝脏组分的体内同种异体反应性。AIM II： 小鼠重建的SCID模型（SCID-mu）的开发 移植研究。目的III：测定小鼠细胞和 细胞因子对小鼠肝脏细胞成分的反应，使用SCID- mu模型与完整BALB/c宿主相比。目标四：发展 用于移植研究的SCID-hu模型。目的五：确定人类 细胞和细胞因子对人肝脏细胞成分的反应。

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.