SOLUBLE MHC ANTIGENS IN TRANSPLANTATION TOLERANCE

描述：目前临床器官移植的成功 由于需要免疫抑制药物， 下调免疫系统。器官移植的改进 将可能基于供体特异性免疫抑制的方法， 这是指抑制淋巴细胞特异性地 针对主要组织相容性复合体（MHC）抗原的免疫抑制剂。 器官捐献者通过这种类型的治疗， 表达外源MHC抗原的供体组织下调， 器官排斥，但免疫力，以抵御常见的微生物和任何 新产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 供体MHC I类抗原给受体接近器官移植的时间 移植为了支持这一理论， 与其他器官相比，肝脏移植可能是由于 肝脏产生大量分泌供体的特殊能力 移植后即刻的MHC I类抗原。因为其他 器官表达膜结合的MHC I类抗原，但很少或没有表达， 分泌抗原，MHC抗原形式可能是参与的关键因素 诱导供体特异性无反应性。一直难以 研究分泌型和膜结合型MHC的免疫学效应 I抗原，因为获得足够数量的纯分子 从粗提取物中提取的量有限。然而，基因的最新发展 转让技术开辟了研究这些问题的新途径， 问题.在本研究中，潜在的捐助者特异性 分泌型与膜结合型大鼠的下调免疫效应 MHC I类抗原将通过转移编码 供体特异性分子进入受体肝细胞。在 此外，分泌的供体大鼠MHC I类/IgG融合蛋白的作用 将检测分子（组织溶素）。淋巴细胞 将暴露于不同形式的供体MHC I类抗原， 通过测定抗供体抗体， 细胞毒性和辅助T细胞活性。遗传改变的肝细胞 或将在围手术期向心脏内施用组织纤维素 移植受体，以确定体内的影响，不同的 供体MHC抗原。这些实验的结果将 有助于了解供体可溶性MHC的潜力， 抗原诱导和维持MHC特异性免疫 无反应性，并可能最终导致临床发展 在移植中诱导供体特异性耐受的疗法。

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.