ALLOGRAFT RESPONSE TO LIVER TISSUE

同种异体移植物对肝组织的反应

• 批准号: 2064353
• 负责人: Nancy Ascher
• 金额: $ 13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1995-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2064353
• 关键词: SCID mouse; antigen presentation; cell sorting; cellular immunity; cytokine; cytotoxicity; gene expression; histocompatibility antigens; host organism interaction; human tissue; immunosuppression; laboratory mouse; liver cells; liver transplantation; polymerase chain reaction; tissue donors; transplant rejection; whole body irradiation effect

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.

目前的提议代表着我们调查的继续 探讨同种异体移植排斥反应的机制。我们将专注于 肝细胞成分刺激同种异体移植物的能力 反应，以更好地了解同种异体肝移植的机制(S) 排斥反应和肝细胞移植的潜力。这些 实验最初将在小鼠模型中进行， L的好处)明确的遗传学2)强烈的同种异体移植反应3) 免疫缺陷动物的可用性4)我们对它们的熟悉程度 模型和技术。然而，我们的最终目标是理解 人同种异体肝移植排斥反应的机制。为了解决这个问题 人类对体内同种异体抗原的反应，研究人员不得不研究 移植物的组织学或从外周血中获取细胞或细胞因子 或者是当地的贪污环境。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 感觉到我们的工作延伸到关于 人体细胞对肝脏成分的反应需要发展 移植研究的SCID-HU模型。小白鼠的潮汐发育 重组的SCID(SCID-MU)是这一进程的合乎逻辑的第一步。 将SCID-MU的反应与完好的宿主进行比较的理由 这是a)我们可以确定两者的细胞反应是否 在面对排斥时具有可比性b)一旦我们建立了细胞 与完整的小鼠相比，我们可以省略在SCID-MU中看到的反应 细胞群被认为对排斥反应不是必需的 重建。这可能有助于定义对以下各项至关重要的单元 C)同样，细胞因子谱在面对 排斥反应有助于确定必要的细胞因子。 拒绝。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细胞已经被证明 选择供体反应细胞的特定克隆。另外，我们希望 使用该模型来定义人体对人体肝脏的反应。这些 研究旨在确定局部和全身细胞和 对肝脏成分的细胞因子免疫反应。此外，贩卖人口 将建立这些模型中免疫活性细胞的模式。 目的I：测定MHC抗原表达对体外和体外培养细胞的影响 体内对小鼠肝脏成分的同种异体反应性。目标二： 小鼠重组SCID模型(SCID-MU)的建立 移植研究。目的三：测定小鼠细胞和 细胞因子对小鼠肝脏细胞成分的反应 MU模型与完整的BALB/c宿主比较。目标四：发展 SCID-HU模型用于移植研究。目标五：确定人类 人肝细胞成分对细胞和细胞因子的反应。

项目成果

beta-2 Microglobulin gene disruption prolongs murine islet allograft survival in NOD mice.

• 发表时间: 1994-04
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: R. Osorio;N. Ascher;J. Melzer;P. Stock

Lack of class II antigen expression on hepatocytes profoundly affects CTL development in vitro and in vivo.

肝细胞上 II 类抗原表达的缺乏深刻影响 CTL 的体外和体内发育。

• 发表时间: 1991
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Clemmings,SM;Alan,TJ;Bumgardner,GL;Ascher,NL
• 通讯作者: Ascher,NL

Enhancement of islet allograft survival in mice treated with MHC class I specific F(ab')2 alloantibody.

用 MHC I 类特异性 F(ab)2 同种抗体治疗的小鼠的胰岛同种异体移植物存活率增强。

• 发表时间: 1994
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Osorio,RW;Ascher,NL;Melzer,JS;Stock,PG
• 通讯作者: Stock,PG

Demonstration of local immunosuppression with methylprednisolone in the sponge matrix allograft model.

在海绵基质同种异体移植模型中展示甲基泼尼松龙的局部免疫抑制。

• DOI: 10.1097/00007890-199108000-00026
• 发表时间: 1991
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Freise,CE;Clemmings,S;Clemens,LE;Alan,T;Ashby,T;Ashby,E;Burke,EC;Roberts,JP;Ascher,NL
• 通讯作者: Ascher,NL

IL-2 and IL-5 gene expression in response to alloantigen in liver allograft recipients and in vitro.

在同种异体肝移植受者和体外，IL-2 和 IL-5 基因表达对同种异体抗原的反应。

• DOI: 10.1097/00007890-199305000-00042
• 发表时间: 1993
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Martinez,OM;Villanueva,JC;Lake,J;Roberts,JP;Ascher,NL;Krams,SM
• 通讯作者: Krams,SM