CYTOKINE REGULATION OF REJECTION IN VIVO

大多数关于同种异体移植物体内排斥反应的概念是由 从体外发生的现象推断。 述海绵基质 同种异体移植物是研究体内排斥过程的非常合适的模型。 海绵同种异体移植物中的发现在许多方面与 常见的体外范例，如细胞因子在细胞增殖中的中心作用， 诱导CTL成熟;然而，一些非常重要的差异 涌现 发现了特异性致敏的TH和CTL，但T细胞 增殖在体内几乎不存在，表明克隆扩增 反应性细胞并不突出。 此外，最关键的 细胞因子被认为是负责扩增和成熟的 体外特异性致敏的T细胞克隆（IL-2、IL-4、IFNg）不能 通过生物测定法检测。 最近发现的TH 1和TH 2亚型， 辅助性T细胞，能够分泌有限的和T细胞亚群特异性的 细胞因子谱，可能揭示了这种差异，因为 海绵基质同种异体移植物的细胞因子模式更类似于TH 2 优势大于TH 1。 因为海绵中细胞因子表达的数据 体内基质同种异体移植模型是非常不完整的， 拟议的项目是研究细胞因子环境， 各种亚群特异性T细胞在体内成熟和分化 海绵基质同种异体移植。 为了实现这一目标，选择了一组TH 1和 TH 2细胞因子将定量（生物测定、ELISA、信使RNA）， 海绵同种异体移植物，平行研究将表征体外 浸润细胞的功能。 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。 海绵基质就像一个皮肤移植物，排斥反应发生在 在伤口急性炎症反应的背景下， 同种异体移植器官的相对隔离。 因此可以 分析急性炎症对细胞凋亡的影响， 免疫力 第二个目的是为了说明存在于 可能调节子集的海绵基质同种异体的环境 特异性T细胞功能。 重点将放在许多可能的几个 炎症因子（PGE_2，TNF-α，TGF-β）可能调节 体内同种异体移植物反应，其中一些可能会导致意想不到的 观察到的细胞和细胞因子应答模式。 更好地理解 体内排斥反应的调节将使更合理的 移植的实施，排斥反应的早期诊断，以及 精确利用抗排斥治疗。

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.