Responsiveness and non-responsiveness to transfused RBCs in mice and humans.

背景：某些输血受者产生具有临床意义的红细胞同种异体抗体的原因尚不清楚。 在抗体(“响应者”)之后，还有其他抗体被输注数百次，但没有产生任何可检测到的 同种异体抗体(“无反应者”)。我们发现受者在接受治疗时的炎症状态 RBC输注，结合受者感知1型干扰素的能力，在 在我们的简化论小鼠模型中确定应答者/非应答者状态。此外，最近对 人类认为，炎症/同种异体免疫之间的联系超越了老鼠，尽管存在遗传变量 也必须考虑。 中心假设：我们假设炎症(特别是1型干扰素的诱导和感觉)和 遗传因素共同决定了哪些输血者会在RBC后形成同种异体抗体 输血，无应答者可能会有耐受性，而不仅仅是对红细胞抗原一无所知。这个 建议的研究利用简化的小鼠模型，献血者表达真实的人类血液 组抗原血糖素A(HGPA)或Kel糖蛋白，并与遗传相同的受体产生 只有当输血时有佐剂存在或有能力感知干扰素时，才能产生红细胞同种抗体。在……里面 对应答和无应答小鼠早期免疫激活事件的联合体内深入研究 应答者和非应答者的CD4+T细胞亚群表型、功能和转录组的体外研究 响应人类，寻求增加关于红细胞同种异体免疫的知识。 特定目的1：研究小鼠体内的哪种受体细胞群(S)介导对 输注的红细胞。 特定目的2：探讨小鼠无反应性发生的机制(S) 在输血后。 具体目标3：研究应答者和无应答者的CD4+T细胞的差异。

Background: It remains unclear why certain transfusion recipients make clinically significant RBC alloantibody after antibody (“responders”), yet others are transfused hundreds of times without generating any detectable alloantibodies (“non-responders”). We have discovered that the recipient inflammatory status at the time of RBC transfusion, in combination with the ability of the recipients to sense type 1 interferons (IFN), are critical in determining responder/non-responder status in our reductionist murine models. Further, recent studies in humans suggest that the inflammation/alloimmunization connection transcends mice, though genetic variables must also be considered. Central Hypothesis: We hypothesize that inflammation (specifically type 1 IFN induction and sensing) and genetic factors together determine which transfusion recipients will form alloantibodies following RBC transfusion, with non-responders possibly being tolerant and not simply ignorant of RBC antigens. The proposed studies utilize reductionist murine models, with blood donors expressing the authentic human blood group antigens glycophorin A (hGPA) or KEL glycoprotein, and with genetically identical recipients generating RBC alloantibodies only when transfusion occurs in the presence of an adjuvant or an ability to sense IFNs. In depth in vivo studies of early immune activation events in responder and non-responder mice, in combination with ex vivo studies of CD4+ T-cell subset phenotype, function, and transcriptome in responder and non- responder humans, seek to increase knowledge of RBC alloimmunization. Specific Aim 1: To investigate which recipient cell population(s) in mice mediate responsiveness to transfused RBCs. Specific Aim 2: To investigate the mechanism(s) through which non-responsiveness in mice occurs following transfusion. Specific Aim 3: To investigate differences in CD4+ T-cells in responder and non-responder humans.