Immunobiology of Alloimmunization by Platelet Transfusion

血小板输注同种免疫的免疫生物学

• 批准号: 10418747
• 负责人: JAMES C. ZIMRING
• 金额: $ 55.06万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418747
• 关键词: Affect; Alloantigen; Allogenic; Alloimmunization; Animals; Antibodies; Antibody Response; Antigens; Area; Biological Models; Blood Cells; Blood Platelets; CD4 Positive T Lymphocytes; Cell Therapy; Cellular biology; Cessation of life; Data; Disease; Dissection; Engineering; Excision; Exposure to; Female; Functional disorder; Generations; Goals; HLA Antigens; Hemorrhage; Hemostatic function; Human; Immune response; Immune system; Immunity; Immunization; Immunize; Immunobiology; Immunologics; Inherited; Investigation; Isoantibodies; Kinetics; Lead; Leukocytes; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Mediating; Medical; Modeling; Modification; Morbidity - disease rate; Multigravidities; Mus; Organ Transplantation; Patients; Persons; Platelet Transfusion; Population; Population Study; Pregnancy; Randomized Controlled Trials; Refractory; Research Proposals; Residual state; Resources; Rest; Risk Factors; Series; Severities; T cell response; Testing; Thrombocytopenia; Transfusion; Transplantation; Variant; base; cellular engineering; cost; fetal; immunogenicity; immunoregulation; improved; in utero; innovation; life-sustaining therapy; mortality; mouse model; novel; novel therapeutics; patient population; personalized medicine; precision medicine; prevent; response; tool; translational approach

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.

项目摘要 血小板的输血是对导致血小板减少症的多种疾病的重要生命疗法。 然而，血小板输血也可能导致体液同种异体免疫，主要是人类白细胞 抗原（HLA）。通过对多种同种抗原的免疫，患者可以对血小板难治 输血，导致艰难的支持血小板输血需求，在极端情况下可以消除 血小板是一种可行的疗法，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障碍，在某些情况下使患者没有资格进行移植，或者 如果它们确实被移植，导致动力学和/或排斥的严重程度增加。多格拉维女性 特别容易容易出现同种免疫 - 妊娠似乎是随后的同种免疫 血小板输血。这是在许多设置中对HLA的同种免疫化是一个重大问题。虽然 血小板的白细胞释放率降低了同种异体免疫的发生率，残留免疫学仍然很大。 重要的是，有挑衅性的数据使不同的白细胞子集对免疫学的影响有所不同（有些 促进免疫力和其他抑制）。那就大量去除白细胞可能会消除抑制作用 （以及免疫）种群。对不同白细胞的差异效应的详细理解 子集将允许血小板单元进行更复杂的工程，以选择性修改 白细胞组成，如果可以去除免疫子集并抑制保留的子集。这样的 信息在血小板输血背景之外的细胞疗法中也可能具有很大的效用。这 提案利用了一种创新，新颖和可拖动的鼠模型，该模型允许对 不同的白细胞亚群对同种免疫的相对贡献。我们已经使用了这个平台 观察到，在诱导的免疫反应中，MHC同种抗原之间存在协调。 根据不匹配的上下文，将同一个同具有差异化的同种抗原释放，打开大门 在个性化的时代，复杂的匹配/不匹配策略用于输血和移植 药品。我们还发现，在小鼠中，就像人类一样，怀孕素数以随后增加 对输血的同种异体免疫反应率。我们提出了两个具体目标，重点是细胞机制 对幼稚的接受者和怀孕的主要接受者中不同白细胞子集的同种异体免疫反应 分别。我们已经融入了这种方法，进一步分析了不匹配的背景如何改变 给定同种抗原的免疫原性，以扩大我们的初始发现。为此生成的模型 建议在小鼠中使用天然发生的MHC同型物质，但要关注特定的同具有抗原剂 边缘工具可用于对同种反应性CD4+ T细胞生物学和 同种抗体产生。总体而言，拟议的研究将新工具与创新的假设相结合 在PLT输血和细胞疗法的背景下，询问与同种异体免疫有关的机械问题。

项目成果

In utero exposure to alloantigens primes alloimmunization to platelet transfusion in mice.

• DOI: 10.1111/trf.16224
• 发表时间: 2021-03
• 期刊: Transfusion
• 影响因子: 2.9
• 作者: Poston JN;Jash A;Hannan LM;Hay AM;Usaneerungrueng C;Howie HL;Kapp LM;Zimring JC
• 通讯作者: Zimring JC