Immunobiology of Alloimmunization by Platelet Transfusion

项目摘要 输注血小板是许多导致血小板减少症的疾病的重要生命维持疗法。 然而，血小板输注也可导致体液同种免疫，主要是人类白细胞 抗原（HLA）。通过对多种同种异体抗原的免疫，患者可变得对血小板免疫难治。 输血，导致难以支持血小板输注需求，在极端情况下， 血小板作为可行的疗法，导致出血的发病率和/或死亡率。抗HLA同种抗体 也可能是移植的实质性障碍，在某些情况下使患者不适合移植，或 如果他们得到移植，导致增加的动力学和/或排斥反应的严重性。多次妊娠雌性 特别倾向于同种免疫-怀孕似乎为随后的同种免疫做好准备， 血小板输注因此，HLA的同种异体免疫在许多情况下是一个重要的问题。虽然 血小板的白细胞减少降低了同种异体免疫率，但残余免疫力仍然很大。 重要的是，有挑衅性的数据表明，不同的白细胞亚群对免疫力的影响不同（一些 促进免疫和其他抑制）。因此，大量去除白细胞可以去除抑制细胞增殖的细胞因子。 (as以及免疫）人群。详细了解不同白细胞的不同作用 亚群将允许血小板单位的更复杂的工程化， 白细胞组成，如果可以去除免疫亚群并保留抑制亚群。等 这些信息在血小板输注范围之外的细胞治疗中也具有很大的效用。这 该提案利用了一种创新的，新颖的，易于处理的小鼠模型，该模型允许详细解剖 不同白细胞亚群对同种免疫的相对贡献。我们已经利用这个平台， 观察到MHC同种异体抗原在诱导免疫应答中存在协同性; 同种异体抗原的同种异体免疫基于错配的背景而不同，从而打开了 在个性化时代，输血和移植的复杂匹配/错配策略 药我们还发现，在小鼠中，就像在人类中一样，怀孕为随后增加的 同种异体输血免疫应答率我们提出了两个具体的目标，重点是细胞机制 在初次接受者和妊娠致敏接受者中对不同白细胞亚群的同种免疫应答， 分别我们在这种方法中进一步分析了不匹配的背景如何改变 免疫原性的一个给定的同种异体抗原，扩大我们的初步研究结果。为此生成的模型 一项提案使用小鼠中天然存在的MHC同种异体抗原，但重点是切割 边缘工具可用于对同种异体反应性CD 4 + T细胞生物学和 同种抗体生成。总的来说，拟议的研究将联合收割机新工具与创新假设相结合， 在PLT输血和细胞疗法的背景下，提出与同种免疫相关的机制问题。

Project Summary Transfusion of platelets is a vital life-sustaining therapy for numerous diseases that result in thrombocytopenia. However, platelet transfusion can also result in humoral alloimmunization, predominantly to human leukocyte antigens (HLA). With immunization to multiple alloantigens, patients can become refractory to platelet transfusion, resulting in difficulty supporting platelet transfusion needs, and in extreme cases can eliminate platelets as a viable therapy, leading to morbidity and/or mortality from hemorrhage. Anti-HLA alloantibodies can also be substantial barriers to transplantation, rendering patients ineligible for transplant in some cases, or if they do get transplanted, leading to an increased kinetics and/or severity of rejection. Multigravid females are particularly prone to alloimmunization – pregnancy appears to prime for subsequent alloimmunization to platelet transfusion. Thus, alloimmunization to HLA is a significant problem in a number of settings. Although leukoreduction of platelets has reduced rates of alloimmunization, residual immunity remains substantial. Importantly, there are provocative data that distinct leukocyte subsets affect immunity differently (some promoting immunity and others suppressing). Thus, the bulk removal of leukocytes may remove suppressing (as well as immunizing) populations. A detailed understanding of the differential effects of distinct leukocyte subsets would allow a more sophisticated engineering of platelet units with regards to selective modification of leukocyte composition, if immunizing subsets can be removed and suppressing subsets retained. Such information may also be of great utility in cellular therapies outside the context of platelet transfusion. This proposal utilizes an innovative, novel, and tractable murine model, that allows a detailed dissection of the relative contribution of different leukocyte subsets to alloimmunization. We have already used this platform to make the observation that there is cooperativity between MHC alloantigens in inducing an immune response; alloimmunization to the same alloantigen differs based upon the context of the mismatch, opening the door to sophisticated matching/mismatching strategies for transfusion and transplantation in an era of personalized medicine. We have also discovered that in mice, as in humans, pregnancy primes for a subsequent increased alloimmune response rate to transfusion. We propose two specific aims, focusing on the cellular mechanisms of alloimmune responses to different leukocyte subsets in naïve recipients and in pregnancy primed recipients, respectively. We have built into this approach a further analysis of how context of mismatch alters immunogenicity of a given alloantigen, to expand on our initial findings. The models generated for this proposal use naturally occurring MHC alloantigens in mice, but focus on specific alloantigens for which cutting edge tools are available to perform a detailed analysis of both alloreactive CD4+ T cell biology and alloantibody generation. In aggregate, the proposed studies combine novel tools with innovative hypotheses to ask mechanistic questions relevant to alloimmunization in the context of PLT transfusion and cellular therapies.