CYTOKINE ROLES IN HEMOLYTIC TRANSFUSION REACTIONS

这个CIDA应用程序的目的是让我能够利用 一个极好的研究培训环境，在这个环境中我可以继续获得 成为独立临床调查员的经验和资历 并继续进行细胞和分子机制的基础研究 输血反应。溶血性输血反应(HTR)是 最令人担心的输血不良后果。我们的知识 参与这些反应的病理生理机制的研究结果如下： 太好了。特别是，人们对炎症的作用知之甚少。 HTR中的细胞因子等介体。为了调查这件事我有 建立了三种HTR体外模型。使用这些工具的初步数据 模型表明，主要炎性细胞因子[肿瘤坏死 因子-β(TNF)、白介素1-β(IL-1)和白介素6(IL-6) 以及趋化/激活细胞因子[单核细胞趋化因子 蛋白-1(MCP)和白介素8(IL-8)]；以及调节细胞因子 白介素1受体拮抗剂(IL-1ra)是对 红细胞不相容。我提出了一系列相关的实验来 进一步描述细胞和免疫学机制涉及的 红细胞血型不合引起的细胞因子产生。使用阻塞 抗体、精致细胞因子的调节及其相互关系 将会被调查。此外，中国的相对贡献 单核细胞、巨噬细胞和库普弗细胞来源的细胞因子对HTR的作用 评估过了。最后，精心设计的细胞因子对内皮细胞的影响 将研究细胞表面粘附性和抗凝血剂特性。 这些研究可能会导致对 HTR背后的病理生理机制，并提示特异性 治疗方式。

The purpose of this CIDA application is to allow me to take advantage of a superb research training environment in which I can continue to acquire experience and credentials to become an independent clinical investigator and pursue basic research into the cellular and molecular mechanisms of transfusion reactions. Hemolytic transfusion reactions (HTR) are one of the most feared adverse consequences of blood transfusion. Our knowledge of the pathophysiologic mechanisms involved in these reactions is incom- plete. In particular, little is known about the role of inflammatory mediators such as cytokines in HTR. To investigate this, I have developed three in vitro models of HTR. Preliminary data using these models indicate that major inflammatory cytokines [tumor necrosis factor-beta(TNF), interleukin-1beta (IL-1), and interleukin-6 (IL-6)]; as well as chemotactic/activating cytokines [monocyte chemoattractant protein-1 (MCP), and interleukin-8 (IL-8)]; and the regulatory cytokine interleukin-1 receptor antagonist (IL-1ra) are produced in response to red cell incompatibility. I propose a set of related experiments to further characterize the cellular and immunologic mechanisms involved in cytokine production induced by red cell incompatibility. Using blocking antibodies, the regulation and interrelationships of elaborated cytokines will be investigated. In addition, the relative contribution of monocytes, macrophages and Kupffer cell-derived cytokines to HTR will be assessed. Finally, the effect of elaborated cytokines on endothelial cell surface adhesion and anticoagulant properties will be studied. These studies will likely lead to a new understanding of the pathophysiologic mechanisms underlying HTR, and suggest specific treatment modalities.