T cell Immunoregulation of alloimmunization in sickle cell disease

描述(由申请人提供)：对于接受治疗性输血的镰状细胞病(SCD)患者来说，红细胞(RBC)异基因免疫可能是一种危及生命的并发症。尽管提供了扩大的抗原匹配的捐赠者红细胞，但由于非洲血统个人的免疫原性抗原高度多态，患者继续产生抗体。因此，在这一患者群体中识别异基因免疫的生物标志物是非常有意义的，这将有助于提前识别最有可能对输血产生抗体的患者，遗传和获得性患者相关因素可能会影响异基因免疫的过程。我们最近报道了调节性T细胞(Treg)和辅助性T细胞(Th)反应的改变，循环Th1(干扰素？)细胞因子，但与非SCD抗体产生者相比，长期输血的SCD抗体产生者IL-10水平较低。我们的初步数据表明，在同种异体免疫的SCD患者中，单核细胞亚群被越来越多地认为是T细胞反应的调节器，在不同程度上抑制调节性T细胞(Treg)的增殖，同时促进效应性T细胞的扩张，部分是通过改变 对IL-12和IL-10的反应性。我们进一步发现，在同种免疫的SCD患者的单核细胞中，以抗炎和免疫抑制作用而闻名的血红素加氧酶I(HO-1)水平较低，并改变了Treg/Th的发育，以氯化血红素为反应，氯化血红素是输血RBC分解产物的替代标记物。我们假设，HO-1水平/活性不足会改变输血后镰刀状天然免疫细胞的抗炎状态，导致致病T细胞对红细胞和同种异体免疫的反应。我们将通过以下具体目标来验证我们的假设：1)剖析SCD同种异体免疫患者T细胞反应的单核细胞控制改变的机制，2)识别SCD同种免疫患者氯化血红素介导的单核细胞极化的机制，3)在一项对每月接受红细胞剥离的SCD患者的纵向研究中，表征同种免疫、低HO-1水平和改变的单核细胞控制Th/Treg增殖之间的关系。我们相信，拟议中的先天性免疫异常的研究不仅将为我们提供关于同种异体免疫SCD患者致病T细胞反应的详细机制了解，这将有助于未来识别同种异体免疫的生物标记物，目标是这些信息最终将有助于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-?) 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.