Innate Immune Receptors that Promote RBC Alloimmunization

项目摘要3 意义：红细胞(RBC)输注是一种强有力的治疗工具。尽管ABO和Rh(D) 与之相匹配，去白细胞的红细胞可诱导针对次要抗原的受体同种异体抗体； 这样的抗体可能导致延迟定位相容的RBC单位用于治疗、溶血性输血反应 或新生儿溶血性疾病。尽管我们在理解上取得了重大进展 管理对病原体的适应性免疫诱导甚至移植的基本规则是什么？ 免疫学决定了某人何时会对异基因单位的红细胞产生反应 未定义。因此，我们无法预测哪些受血者会产生同种异体抗体。识别 调节红细胞上外来抗原免疫的先天免疫细胞和受体将使我们能够 确定输血期间同种免疫的潜在免疫触发因素，并作为延伸，确定抑制的目标 在这些治疗期间，以促进免疫耐受。 创新：我们开发了一个小鼠模型系统，在这个系统中我们可以评估特定的先天因素的作用 异基因红细胞输注过程中的免疫刺激和细胞。这些模型第一次允许我们 解剖产生有害同种免疫所需的特定受体和途径 输血。我们的初步数据强烈表明，病原体的经典感受器，Toll样受体 (TLRs)，也对输注的红细胞作出反应，并指示T和B细胞对RBC来源的抗原激活。 方法/研究人员：使用这些小鼠模型，我们将检验T细胞启动RBC的假设 同种异体抗原在缺乏天然免疫途径的情况下是有缺陷的，因为它消除了 下游信号通路或特定的表面受体。艾森巴特博士在 评估先天免疫受体在塑造T细胞反应中的作用。亨德里克森博士是该领域的领导者 RBC同种异体免疫领域，已经发展了许多广泛使用的小鼠模型来研究这一过程。 在协作中，我们将解决以下具体目标：目标1，确定MyD88 调节对同种异体红细胞的获得性免疫和目的2，确定哪个Toll样受体(S)驱动T细胞- 依赖红细胞同种异体免疫。

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.