T cell Immunoregulation of alloimmunization in sickle cell disease

描述（由申请人提供）：红细胞（RBC）同种异体免疫可能是接受治疗性输血的镰状细胞病（SCD）患者的危及生命的并发症。尽管提供了扩展的抗原匹配的供体RBC，但由于非洲血统个体中免疫原性抗原的高度多态性，患者继续产生抗体。 因此，在这一患者群体中鉴定同种免疫的生物标志物具有极大的意义，并将有助于提前鉴定最有可能在输血后产生抗体的患者。遗传因素以及获得性患者相关因素可能会影响同种免疫的过程。我们最近报告了与SCD非产生者相比，慢性输血SCD抗体产生者的调节性T细胞（Treg）和辅助性T细胞（Th）反应发生改变，循环Th 1（IFN-γ）细胞因子较高，但IL-10水平较低。我们的初步数据表明，在同种免疫的SCD患者中，单核细胞亚群，越来越多地被认为是T细胞应答的调节剂，差异性地抑制调节性T细胞（Treg）增殖，同时通过改变免疫调节性T细胞亚群的表达，部分促进效应性T细胞扩增。 对IL-12和IL-10的反应性。我们进一步鉴定了同种异体免疫SCD患者单核细胞中血红素加氧酶I（HO-1）的较低水平（以其抗炎和免疫抑制作用而闻名），以及对血晶素（输血RBC分解产物的替代标志物）的反应改变了Treg/Th发育。我们假设HO-1的水平/活性不足改变了RBC输注后镰状先天免疫细胞的抗炎状态，导致针对RBC的致病性T细胞应答和同种免疫。我们将通过以下具体目标来检验我们的假设：1）剖析同种异体免疫的SCD患者中T细胞应答的单核细胞控制改变的机制，2）鉴定同种异体免疫的SCD患者中氯化血红素介导的单核细胞极化的机制，和3）表征同种异体免疫，在每月接受红细胞单采术的SCD患者的纵向研究中，HO-1水平降低和Th/Treg增殖的单核细胞控制改变。我们相信，拟议的研究先天免疫异常的方式不仅将为我们提供一个详细的机制理解，有助于同种免疫SCD患者的致病性T细胞反应，这将有助于未来识别同种免疫的生物标志物，目标是这些信息将最终帮助指导这些患者的治疗。

DESCRIPTION (provided by applicant): Red blood cell (RBC) alloimmunization can be a life-threatening complication for patients with sickle cell disease (SCD) receiving therapeutic transfusions. Despite provision of extended antigen-matched donor RBCs, patients continue to develop antibodies due to high degree of polymorphisms in the immunogenic antigens in individuals of African ancestry. Identification of biomarkers of alloimmunization in this patient population is therefore of great interest and will help to identify in advance patients most likelyto make antibodies in response to transfusion Genetic as well as acquired patient-related factors are likely to influence the process of alloimmunization. We recently reported altered regulatory T cell (Treg) and T helper (Th) responses with higher circulating Th1 (IFN-γ) cytokines, but lower IL-10 levels in chronically transfused SCD antibody producers as compared to SCD non-producers. Our preliminary data indicate that in alloimmunized SCD patients, monocyte subsets, which are increasingly recognized as modulators of T cell responses, differentially suppress regulatory T cell (Treg) proliferation while promoting effector T cell expansion in part by altered responsiveness to IL-12 and IL-10. We have further identified lower levels of heme oxygenase I (HO-1), known for its anti-inflammatory and immunosuppressive role, in monocytes from alloimmunized SCD patients and altered Treg/Th development in response to hemin, a surrogate marker for transfused RBC breakdown products. We hypothesize that inadequate levels/activity of HO-1 alters the anti- inflammatory state of the sickle innate immune cells following RBC transfusion, resulting in pathogenic T cell responses against RBCs and alloimmunization. We will test our hypothesis with the following specific aims: 1) to dissect the mechanism of altered monocyte control of T cell responses in alloimmunized patients with SCD, 2) to identify the mechanisms of hemin-mediated monocyte polarization in alloimmunized patients with SCD, and 3) to characterize the association between alloimmunization, low HO-1 levels and altered monocyte control of Th/Treg proliferation in a longitudinal study of SCD patients receiving monthly erythrocytopheresis. We believe that the proposed studies the ways in which innate immune abnormalities can will not only provide us with a detailed mechanistic understanding of contribute to pathogenic T cell responses in alloimmunized SCD patients, which will help future identification of biomarkers of alloimmunization with the goal that this information will ultimately help guide therapy in these patients.