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，红细胞（RBC）同种异体免疫可能是危及生命的并发症。尽管提供了抗原匹配的供体红细胞，但由于非洲血统个体的免疫原性抗原高度多态性，患者继续产生抗体。因此，在该患者群体中鉴定同种异体免疫的生物标志物具有很大的兴趣，并将有助于提前确定最有可能在输血反应中产生抗体的患者。遗传因素以及获得性患者相关因素可能影响同种异体免疫的过程。我们最近报道了慢性输注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Th1 （IFN-γ）细胞因子升高，但与非SCD抗体产生者相比，IL-10水平降低。我们的初步数据表明，在同种异体免疫的SCD患者中，单核细胞亚群越来越被认为是T细胞反应的调节剂，不同程度地抑制调节性T细胞（Treg）的增殖，同时部分通过改变诱导效应T细胞扩增

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.