Inflammatory control of erythropoiesis in sickle disease

描述(由申请人提供)： 慢性病贫血(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 已经清楚地证明ACD是细胞因子的结果 调节免疫和炎症过程。相比之下，镰状细胞性贫血 是遗传缺陷产生的单一氨基酸变化的结果 改变脱氧血红蛋白的溶解度。在同一时期 时至今日，人们已经认识到镰刀的临床表现 综合征是由一系列过程引起的，包括激活 发炎。伴随着细胞因子的高度炎症状态 在镰状细胞病患者中可以证明产生了这种物质。然而， 镰刀状红细胞的独特特性(包括持久性 CD36的表达)改变红系反应的特征 细胞因子。文献回顾表明，CD36的持久性处于高水平 水平是镰刀状红细胞独有的，并有助于它们的粘附性 属性。在我们的初步数据中，我们已经证明CD36是一种 正向红细胞生成调节剂。如上所述，细胞因子 炎症反应的中介物产生ACD，类似的机制可以 与镰刀病有牵连。基于文献中的数据和我们的 初步结果报告如下，推测CD36的表达 保护镰状红系祖细胞免受细胞因子的抑制 持续表达CD36的祖细胞具有选择性生长 在存在抑制性细胞因子方面的优势。这将导致 优先生产表达CD36的红细胞，然后更多 可能参与血管内粘连。与细胞因子有关的细胞因子 因此，炎症反应会增加血管形成的频率。 通过增加潜在追随者的频率来改变事件 红血球。这一假设将通过以下具体的 目的：特定的目的1将确定CD36表达的差异 来自镰状细胞患者和前体细胞的祖细胞，以及来自对照的祖细胞。 在特定目标2中，对细胞因子抑制的敏感性差异 镰刀和对照CFU-E之间的差异，以及这些差异的程度 可以归因于CD36表达的差异，将其定义。在……里面 具体目标3，FA6-152将用于表征CFU-E对来自 镰刀患者对CD36的激活，并确定CD36是如何激活的 也可以通过抑制细胞因子改变祖细胞抑制的模式 作为重组人促红细胞生成素对这些进程的贡献；具体目标4将 描述镰状细胞患者骨髓中局部细胞因子的产生， 以及它与红系CD36表达和临床表型的关系。

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.