CYTOKINE REGULATION OF REJECTION IN VIVO

关于同种异体移植物在体内如何排斥的大多数概念都是由 从发生在体外的现象进行推断。海绵基质 同种异体移植物是研究体内排斥反应过程的理想模型。 在同种异体海绵移植物中的发现在许多方面与 常见的体外范例，如细胞因子在体内的中心作用 诱导CTL成熟；然而，一些非常重要的差异 出现了。发现了特异性致敏的TH和CTL，但T细胞 体内几乎没有增殖，这表明克隆性扩张 反应细胞的数量并不突出。此外，最关键的是 被认为是导致血管扩张和成熟的细胞因子 体外特异性致敏的T细胞克隆(IL-2、IL-4、IFNG)不能 用生物检验法检测。新近发现的TH1和TH2亚型 辅助性T细胞，能够分泌有限的T细胞亚群 细胞因子的光谱，可能会为这种差异提供一些线索，因为 同种异体海绵基质移植物的细胞因子模式更类似于TH2 比TH1更具优势。因为海绵中细胞因子表达的数据 体内同种异体基质移植模型非常不完整，这是本研究的首要目标 拟议的项目是调查在其中的细胞因子环境 各种亚群特异性T细胞在体内成熟和分化 海绵矩阵同构分析为了实现这一目标，一组精选的TH1和 Th2细胞因子(生物测定、ELISA、信使RNA)将在 同种异体海绵移植，平行研究将在体外表征 侵袭细胞的功能。然后应该可以测试 某些细胞因子在体内细胞免疫成熟中的作用。 海绵基质就像皮肤移植一样，排斥反应发生在 伤口的急性炎症反应的背景，而不是 异体器官移植的相对隔离。因此，有可能 分析急性炎症对细胞进化的影响 豁免权。第二个目标是调查存在于 海绵基质异体移植的环境可能调节亚群- 特定的T细胞功能。重点将放在许多可能性中的几个 炎症因子(前列腺素E_2、肿瘤坏死因子-a、转化生长因子-b)可能调节 体内同种异体移植反应，其中一些可能会导致意想不到的 观察到细胞和细胞因子反应的模式。更好地理解 对体内排斥反应的调节将允许更理性的 移植的实施，排斥的早期诊断，以及 抗排斥治疗的精确应用。

Most concepts of how allografts reject in vivo have been formulated by extrapolation from phenomena which occur in vitro. The sponge matrix allograft is a well-suited model to study the rejection process in vivo. The findings within the sponge allograft are in many ways consistent with common in vitro paradigms, such as the central role of cytokines in inducing maturation of CTL; however, some very important differences have emerged. Specifically sensitized TH and CTL are found, but T cell proliferation is virtually absent in vivo, suggesting that clonal expansion of reactive cells is not prominent. Furthermore, the most critical cytokines thought to be responsible for the expansion and maturation of specifically sensitized clones of T cells in vitro (IL-2,IL-4, IFNg) cannot be detected by bioassay. The recent discovery of TH1 and TH2 subtypes of helper T cells, capable of secreting a limited and T cell subset-specific spectrum of cytokines, may shed some light on this discrepancy, because the cytokine pattern of the sponge matrix allograft more resembles TH2 predominance than TH1. Because data on cytokine expression in the sponge matrix allograft model in vivo is very incomplete, the first aim of this proposed project is TO INVESTIGATE THE CYTOKINE ENVIRONMENT IN WHICH VARIOUS SUBSET-SPECIFIC T CELLS MATURE AND DIFFERENTIATE IN VIVO AFTER SPONGE MATRIX ALLOGRAFTING. To meet this aim, a selected group of TH1 and TH2 cytokines will be quantitated (bioassay, ELISA, messenger RNA) in the sponge allograft, and parallel studies will characterize the in vitro functions of infiltrating cells. It should then be possible to test the roles of certain cytokines in the maturation of cellular immunity in vivo. The sponge matrix is like a skin graft in that rejection takes place in the context of an acute inflammatory reactions to a wound instead of the relative isolation of an organ allograft. Therefore it is possible to analyze the influence of acute inflammation on the evolution of cellular immunity. The second aim is TO INVESTIGATE SEVERAL FACTORS PRESENT IN THE ENVIRONMENT OF THE SPONGE MATRIX ALLOGRAFT WHICH MIGHT REGULATE SUBSET- SPECIFIC T CELL FUNCTIONS. Focus will be placed on a few of many possible inflammatory factors (PGE2, TNF-a, TGF-b) which might modulate the allograft response in vivo, some of which might cause the unexpected pattern of cellular and cytokine response observed. A better understanding of the regulation of rejection in vivo will allow more rational implementation of transplantation, earlier diagnosis of rejection, and precise utilization of anti-rejection therapies.