The role of type 1 interferon in regulating alloimmune responses to transfused red blood cells

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Abstract: With approximately 5 million Americans transfused per year, red blood cell (RBC) transfusion is the most common procedure performed in United States hospitals. RBC transfusion exposes recipients to hundreds of non-ABO antigens that are not matched between donors and recipients. This exposure can lead to production of antigen-specific alloantibodies, which can cause potentially fatal hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Currently, there are no means to predict which recipients have an elevated risk of alloimmunization. Identification of at-risk patients would allow for interventions to inhibit alloimmunization and its detrimental effects. Thus, identifying factors that determine which individuals will develop RBC alloimmune responses has been recognized as a research priority in transfusion medicine by the NHLBI. One contributing factor is the inflammatory state of the transfusion recipient. Recent studies have reported an increased frequency of alloimmunization in patients with disseminated viral infections or inflammatory diseases, including multiple autoimmune diseases. However, the molecular mechanisms underlying this association, including the role of critical inflammatory cytokines, are poorly understood. Given that type 1 interferons (IFNα/β) regulate antiviral immunity and autoimmune pathology, we hypothesize that IFNα/β signaling regulates alloimmune responses to RBC antigens. Preliminary data indicate that IFNα/β production and signaling, specifically in B cells, is required for alloimmunization in mice. Using a murine model of transfusion, we aim to identify mechanisms underlying transfusion-induced IFNα/β production (Aim 1) and B cell responses to IFNα/β signaling during RBC alloimmunization (Aim 2). Findings will provide a potential mechanistic basis for past observations of inflammation-induced alloimmunization. In addition, results may identify potential targets of laboratory tests that could improve prediction of alloimmunization. The candidate is a post-doctoral fellow in Laboratory Medicine. He proposes to gain mentored research experience and career development training as a physician-scientist in Transfusion Medicine. The project will provide experience in applying innate immune mechanisms to regulation of RBC alloimmune responses. Training will be conducted at Yale School of Medicine under the mentorship of leaders in Transfusion Medicine and innate immunity. The candidate will develop experimental and analytical skills, including microscopic analysis of lymphoid tissue, quantification of B cell processes in vivo, and acquisition and analysis of high-throughput RNA sequencing data. He will complete a career development plan that includes coursework in inflammation, biostatistics, and translational immunology. His career directions will be shaped by his participation in local and international associations of immuno-hematology research. Such training will be instrumental to the applicant's goal of generating and translating immunologic findings into improved transfusion safety as an independent investigator.