Innate Immune Receptors that Promote RBC Alloimmunization

项目3 意义：红细胞（RBC）输注是一种强大的治疗工具。尽管ABO和Rh（D） 匹配的、白细胞减少的RBC可导致诱导针对次要抗原的受体同种抗体; 这些抗体可能导致延迟定位用于治疗的相容RBC单位、溶血性输血反应 或新生儿溶血性疾病。虽然我们对人类的认识有了很大的进步， 控制诱导对病原体的适应性免疫甚至移植的基本规则， 免疫学上决定某人何时对同种异体红细胞单位作出反应的机制在很大程度上仍然存在。 未定义。因此，我们无法预测哪些输血受者将产生同种抗体。识别 先天性免疫细胞和受体调节免疫对外来抗原的红细胞将使我们能够 识别输血期间同种免疫的潜在免疫触发因素，并作为扩展，靶向抑制 以促进免疫耐受。 创新：我们已经开发了一种小鼠模型系统，在该系统中，我们可以评估特定先天性 同种异体红细胞输注期间的免疫刺激物和细胞。这些模型首次让我们 为了剖析在免疫过程中产生有害的同种异体免疫所需的特异性受体和途径， 输血我们的初步数据有力地表明，病原体的经典传感器，Toll样受体， TLR也对输注的RBC产生应答，并指示T和B细胞对RBC衍生抗原的活化。 方法/研究者：使用这些小鼠模型，我们将检验T细胞致敏RBC 同种异体抗原在缺乏先天免疫途径的情况下是有缺陷的， 下游信号通路或特定的表面受体。Eisenbarth博士拥有丰富的经验， 评估先天免疫受体在塑造T细胞反应中的作用。亨德里克森博士是一个领导者， 红细胞同种异体免疫领域，并已开发出许多广泛使用的小鼠模型来研究这一过程。 在合作中，我们将解决以下具体目标：目标1，确定MyD 88 调节对同种异体红细胞和Aim 2的适应性免疫，确定哪种Toll样受体驱动T细胞- 依赖性RBC同种免疫。

Summary Project 3 Significance: Red blood cell (RBC) transfusion is a powerful therapeutic tool. Despite ABO and Rh(D) matching, leukoreduced RBCs can lead to the induction of recipient alloantibodies against minor antigens; such antibodies may result in delay locating compatible RBC units for therapy, hemolytic transfusion reactions or hemolytic disease of the newborn. Although there have been significant advances in our understanding of the basic rules that govern the induction of adaptive immunity to pathogens and even transplantation, what immunologically determines when someone will respond to an allogeneic unit of RBCs remains largely undefined. Consequently, we cannot predict which transfusion recipients will develop alloantibodies. Identifying the innate immune cells and receptors that regulate immunization to foreign antigens on RBCs will enable us to identify potential immune triggers of alloimmunization during transfusion and, as an extension, targets to inhibit during these therapies to promote immunological tolerance. Innovation: We have developed a murine model system in which we can evaluate the role of particular innate immune stimuli and cells during allogeneic red blood cell transfusion. These models allow us for the first time to dissect the specific receptors and pathways required for the generation of detrimental alloimmunity during transfusion. Our preliminary data strongly suggest that classic sensors of pathogens, the Toll-like receptors (TLRs), also respond to transfused RBCs and instruct the activation of T and B cells to RBC-derived antigens. Approach/Investigators: Using these murine models we will test the hypothesis that T cell priming to RBC alloantigens is defective in the absence of innate immune pathways by eliminating combinations of downstream signaling pathways or particular surface receptors. Dr. Eisenbarth has extensive experience in evaluating the role of innate immune receptors in shaping T cell responses. Dr. Hendrickson is a leader in the RBC alloimmunization field and has developed many of the widely used murine models to study this process. In collaboration, we will address the following specific aims: Aim 1, Determine the mechanism by which MyD88 regulates adaptive immunity to allogeneic RBCs and Aim 2, Identify which Toll-like receptor(s) drive T cell- dependent RBC alloimmunization.