Inflammatory control of erythropoiesis in sickle disease

描述（由申请人提供）： 慢性病性贫血（ACD）是最常见的血液病之一， 临床医学中遇到的症状。在过去的十年里，研究 已经清楚地确定，ACD是细胞因子的结果， 介导免疫和炎症过程。相比之下，镰状细胞性贫血 是一种遗传缺陷的结果，它产生一个单一的氨基酸变化， 改变脱氧血红蛋白的溶解度。与前一年同月比较 时间，它已成为公认的临床表现镰刀 综合征由一系列过程引起，包括激活 炎症炎症状态加剧，随之产生细胞因子 可以在镰状细胞病患者中证实。然而，在这方面， 镰状红细胞的独特特征（包括持续的 CD 36的表达）改变红系细胞对 细胞因子文献回顾表明，CD 36在高水平的持续存在， 水平是镰状红细胞所特有的，并有助于它们的粘附 特性.在我们的初步数据中，我们已经证明了CD 36是一种 红细胞生成的正调节因子。如上所述，细胞因子 炎症反应的介质产生ACD，类似的机制可以 与镰刀病有关根据文献中的数据和我们的 初步结果报告如下，假设CD 36表达 保护镰状红系祖细胞免受细胞因子抑制， 那些持续表达CD 36的祖细胞具有选择性生长， 在抑制性细胞因子的存在下是有利的。这将导致 优先产生表达CD 36的红细胞， 可能参与血管内粘连。参与的细胞因子 因此，炎症反应会增加血管炎的发生频率， 镰状化事件，通过增加潜在粘附的 红细胞这一假设将通过以下具体测试进行检验： 目的：特异性目的1将确定CD 36表达的差异， 来自镰状细胞患者和前体的祖细胞，以及来自对照的那些。 在特定目标2中，对细胞因子抑制的敏感性差异 镰状细胞和对照CFU-E之间的差异，以及这些差异的程度 可以归因于CD 36表达的差异，将被定义。在 具体目标3，FA 6 - 152将用于表征CFU-E的响应， 镰状细胞患者CD 36活化，并确定CD 36活化 通过抑制性细胞因子改变祖细胞抑制的模式， 作为rhEPO对这些过程的贡献;具体目标4将 表征镰状细胞患者骨髓中的局部细胞因子产生， 以及它如何与红系CD 36表达和临床表型相关。

DESCRIPTION (provided by applicant): The anemia of chronic disease (ACD) is one of the most common hematologic syndromes encountered in clinical medicine. Over the last decade, studies have clearly established that ACD is a consequence of the cytokines which mediate the immune and inflammatory process. In contrast, sickle cell anemia is the result of a genetic defect producing a single amino acid change which alters the solubility of deoxygenated hemoglobin. Over the same period of time, it has become recognized that the clinical manifestations of the sickle syndromes result from a constellation of processes, including activation of inflammation. A heightened inflammatory state with consequent cytokine production can be demonstrated in patients with sickle cell disease. However, the unique characteristics of the sickle erythrocyte (including the persistent expression of CD36) alter the characteristics of the erythroid response to cytokines. Review of the literature suggests that CD36 persistence at high levels is unique to sickle erythrocytes, and contributes to their adhesive properties. In our preliminary data, we have demonstrated that CD36 is a positive regulator of erythropoiesis. As discussed above, the cytokine mediators of the inflammatory response produce ACD, and similar mechanisms can be implicated in sickle disease. Based on data in the literature and on our preliminary results reported below, it is hypothesized that CD36 expression protects sickle erythroid progenitors against cytokine suppression, and that those progenitors which persistently express CD36 have a selective growth advantage in the presence of inhibitory cytokines. This would result in the preferential production of CD36-expressing erythrocytes, which are then more likely to participate in intravascular adhesion. The cytokines involved in the inflammatory response would therefore enhance the frequency of vascular sickling events by increasing the frequency of potentially adherent erythrocytes. This hypothesis will be tested through the following Specific Aims: Specific Aim 1 will identify the differences in CD36 expression between progenitors from sickle cell patients and precursors, and those from controls. In Specific Aim 2, the differences in sensitivity to cytokine inhibition between sickle and control CFU-E, and the extent to which these differences can be attributed to differences in CD36 expression, will be defined. In Specific Aim 3, FA6-152will be used to characterize the response of CFU-E from sickle patients to CD36 activation, and to determine how CD36 activation alters the pattern of progenitor suppression by inhibitory cytokines, as well as the contribution of rhEPO to these processes; and Specific Aim 4 will characterize local cytokine production in the marrow of sickle cell patients, and how it relates to erythroid CD36 expression and to clinical phenotype.