CYTOKINE ROLES IN HEMOLYTIC TRANSFUSION REACTIONS

这个加拿大国际开发署的应用程序的目的是让我利用 一个极好的研究培训环境，我可以继续获得 成为独立临床研究者的经验和证书 并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 输血最可怕的不良后果。 我们的知识 这些反应中涉及的病理生理机制是不一致的， 完全。 特别是，人们对炎症反应的作用知之甚少。 HTR中的细胞因子等介质。 为了调查此事，我 开发了三种体外HTR模型。 初步数据使用这些 模型表明，主要的炎性细胞因子[肿瘤坏死 因子-β（TNF）、白细胞介素-1 β（IL-1）和白细胞介素-6（IL-6）];作为 以及趋化/活化细胞因子[单核细胞趋化因子 蛋白-1（MCP）和白细胞介素-8（IL-8）];以及调节性细胞因子 白细胞介素-1受体拮抗剂（IL-1ra）是响应于 红细胞不相容性 我提出了一组相关的实验， 进一步表征参与的细胞和免疫机制， 红细胞不相容性诱导的细胞因子产生。 使用封闭 抗体，精心制作的细胞因子的调节和相互关系 将被调查。 此外， 单核细胞、巨噬细胞和枯否细胞衍生的细胞因子对HTR的影响将是 评估。 最后，详细研究了细胞因子对内皮细胞的影响。 将研究细胞表面粘附和抗凝血性质。 这些研究可能会导致对 HTR的病理生理机制，并建议具体 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.