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

背景：目前尚不清楚为什么某些输血受者产生具有临床意义的红细胞同种抗体 在抗体（“应答者”）之后，还有一些人输了数百次，而没有产生任何可检测的抗体。 同种抗体（“无应答者”）。我们已经发现，受体在移植时的炎症状态 红细胞输注与受体感受1型干扰素（IFN）的能力相结合， 在我们的还原论小鼠模型中确定应答者/非应答者状态。此外，最近的研究表明， 人类表明，炎症/同种免疫的联系超越了小鼠，尽管遗传变量 也必须加以考虑。 中心假设：我们假设炎症（特别是1型IFN的诱导和感应）和 遗传因素共同决定了哪些输血受者在红细胞输注后会形成同种抗体 输血，无应答者可能是耐受的，而不仅仅是对RBC抗原无知。的 拟议的研究利用简化的小鼠模型，献血者表达真实的人血， 组抗原血型糖蛋白A（hGPA）或KEL糖蛋白，并与遗传上相同的受体产生 只有在存在佐剂或有IFN感应能力的情况下输血时，才会产生RBC同种抗体。在 在应答和非应答小鼠中早期免疫激活事件的深入体内研究， 通过对应答者和非应答者中CD 4 + T细胞亚群表型、功能和转录组的体外研究， 响应者人类，寻求增加RBC同种免疫的知识。 具体目的1：研究小鼠中哪种受体细胞群介导对以下物质的反应性： 输红细胞 具体目的2：研究小鼠发生无反应性的机制 输血后。 具体目标3：研究应答者和非应答者中CD 4 + 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.