T cell Immunoregulation of alloimmunization in sickle cell disease

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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.