PROGRAM PROJECT IN TRANSPLANTATION IMMUNOLOGY

这份提案代表着我们计划的第一次续签申请 移植免疫学项目。这个节目最初的重点是 是关于(A)抗原提呈和(B)免疫细胞的细胞因子调节 功能：移植最重要的两个具体问题 生物学家。目前的提案延续了这一总体重点，但现在 专注于细胞因子免疫生物学的主题，特别是 重点是肿瘤坏死因子和白介素1。项目2跟进了由 罗伯特·施赖伯、凯瑟琳·希恩和保罗·莱西：肿瘤坏死因子和白介素1可以 显著抑制T细胞活化和移植物排斥反应 正常的小鼠。Schreiber和Sheehan现在提议研究细胞和 这种免疫抑制过程的分子基础 这些细胞因子对抗原提呈细胞功能和T细胞的影响 体内和体外发育。由于IL-1拥有如此突出的 在此方案项目中的位置，第三个项目将表征 激活IL-1β的生理机制。在这里，大卫 卓别林将对一种新定义的 一种似乎是蛋白水解性激活所必需的酶 小鼠(和人)IL-1β。项目3将直接应用这些原则 细胞因子生物学已经并将继续从我们的 异种移植和同种异体排斥反应模型的基础研究。 保罗·莱西博士和大卫·沙普博士将扩大他们对 肿瘤坏死因子、白介素1及联合应用转化生长因子β和抗肿瘤坏死因子-γ抑制肿瘤生长的实验研究 胰岛移植排斥反应。该项目可能会提供 通过更好地定义基本的 参与诱导免疫耐受的机制和通过 帮助开发新的、更安全的免疫抑制治疗药物。 因此，这一特定计划项目的总体收益将继续 将基本免疫学概念有效地应用于 移植生物学。

This proposal represents the first renewal application of our program project in transplantation immunology. The original focus of this program was on (a) antigen presentation and (b) cytokine regulation of immune cell function: two specific issues of paramount importance to transplant biologists. The current proposal continues this overall focus but now concentrates on the topic of cytokine immunobiology with particular emphasis on TNF and IL-1. Project 2 follows up an observation made by Robert Schreiber, Kathleen Sheehan and Paul Lacy that TNF and IL-1 can profoundly suppress T cell activation and graft rejection responses in normal mice. Schreiber and Sheehan now propose to study the cellular and molecular basis of this immunosuppressive process by examining the effects of these cytokines on antigen presenting cell function and T cell development in vivo and in vitro. Since IL-1 holds such a prominent position in this program project, the third project will characterize the physiologic mechanism by which IL-1beta is activated. Herein, David Chaplin will perform a detailed molecular analysis on a newly defined enzyme that appears to be uniquely required for proteolytically activating murine (and human) IL-1beta. Project 3 will directly apply the principles of cytokine biology which have been and continue to be obtained from our basic research studies to models of xenograft and allograft rejection. Drs. Paul Lacy and David Scharp will expand their studies on the use of TNF, IL-1 and the combination of TGFbeta and anti-IFNgamma to suppress the rejection of pancreatic islet grafts. This project is likely to provide direct benefits to transplantation biologists by better defining the basic mechanisms involved in the induction of immunologic tolerance and by helping to develop novel and safer immunosuppressive therapeutic agents. Thus, the overall benefit of this particular program project continues to be the efficient application of basic immunologic concepts to the field of transplantation biology.