SOLUBLE MHC ANTIGENS IN TRANSPLANTATION TOLERANCE

描述：目前在临床器官移植方面取得成功 受限于对非特异性免疫抑制药物的需求 下调免疫系统。器官移植的研究进展 可能会基于一种针对捐赠者的免疫抑制方法， 它指的是对特定方向的淋巴细胞的抑制 抗猪瘟病毒主要组织相容性复合体(MHC)抗原 器官移植捐赠者。在这种疗法下，免疫反应对 表达外源MHC抗原的供体组织被下调以防止 器官排斥反应，但免疫力击退常见微生物和任何 新生的癌细胞被保存下来。有证据表明 供体特异性免疫抑制可能通过引入 器官移植时供体MHC-I类抗原给受者 移植。为了支持这一理论，免疫特权与 肝移植与其他器官相比，可能是由于 肝脏产生大量分泌性供体的特殊能力 移植后即刻检测MHC-I类抗原。因为其他人 器官表达膜结合的MHC-I类抗原，但很少或没有 分泌抗原，MHC抗原形式可能是一个关键因素 导致捐赠者特有的无反应。这很难做到 分泌型和膜结合型MHC类分子的免疫效应研究 I抗原，因为获得足够数量的纯分子 从粗提物中提取的量是有限的。然而，基因的最新发展 转移技术为研究这些问题开辟了新的途径 问题。在本研究中，潜在的供体特异性 分泌型与膜结合型大鼠的免疫降调作用(S) MHC I类抗原将通过转移DNA编码来确定 体外将供体特异性分子导入受体肝细胞。在……里面 此外，分泌型供体大鼠MHC-I/Ig G融合的效果 将对分子(组织球蛋白)进行测试。受体品系淋巴细胞 会接触到不同形式的供体MHC I类抗原 培养和免疫效果将通过测量抗供体来比较 细胞毒和辅助性T细胞活性。转基因肝细胞 或者将在围手术期将组织球蛋白注入心脏 以确定移植受者体内不同的影响 供体MHC抗原的形式。这些实验的结果将 有助于理解供体可溶的MHC的潜力 诱导和维持MHC特异性免疫的抗原 无反应，并可能最终导致临床的发展 在移植中诱导供者特异性耐受的治疗。

DESCRIPTION: Success in clinical organ transplantation is currently limited by the need for immunosuppressive drugs that non-specifically down regulate the immune system. Improvements in organ transplantation will likely be based on an approach to donor-specific immunosuppression, which refers to a suppression of lymphocytes directed specifically against the major histocompatibility complex (MHC) antigen of the transplant donor. With this type of therapy the immune response towards donor tissue expressing foreign MHC antigens is downregulated to prevent organ rejection, but immunity to fight off common microorganisms and any newly arising cancer cells is preserved. There is evidence to suggest that donor-specific immunosuppression may be possible by introducing donor MHC class I antigens to the recipient near the time of organ transplantation. In support of this theory immune privilege associated with liver transplants compared to other organs, may be due to the special ability of a liver to produce large quantities of secreted donor MHC class I antigen immediately after transplantation. Since other organs express membrane-bound MHC class I antigen, but little or no secreted antigen, the MHC antigen form may be a critical factor involved in inducing donor-specific unresponsiveness. It has been difficult to study the immunologic effects of secreted and membrane-bound MHC class I antigens because obtaining pure molecules in sufficient quantities from crude extracts was limiting. However, recent developments in gene transfer technology have opened up new approaches to study these questions. In the present study, the potential donor-specific downregulatory immunologic effect(s) of secreted vs. membrane-bound rat MHC class I antigen will be determined by transferring DNA encoding donor-specific molecules into recipient hepatocytes in vitro. In addition, the effects of a secreted donor rat MHC class I/IgG fusion molecule (histoglobulin) will be tested. Recipient strain lymphocytes will be exposed to the different forms of donor MHC class I antigen in culture, and immunologic effects will be compared by measuring anti-donor cytotoxic and helper T-cell activity. Genetically altered hepatocytes or histoglobulin will be administered perioperatively into heart transplant recipients to determine the in vivo effects of the different forms of donor MHC antigen. Results from these experiments will contribute to the understanding of the potential for donor-soluble MHC antigens to induce and maintain MHC-specific immunologic unresponsiveness, and may eventually lead to the development of clinical therapies to induce donor-specific tolerance in transplantation.