Immunobiology of Alloimmunization by Platelet Transfusion

血小板输注同种免疫的免疫生物学

• 批准号: 10192810
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192810
• 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 对于导致血小板减少的多种疾病，输注血小板是一种重要的维持生命的疗法。 然而，血小板输注也可以导致体液免疫，主要是对人类白细胞的免疫。 抗原(人类白细胞抗原)。通过对多种同种异体抗原的免疫，患者可能对血小板产生抵抗力 输血，导致难以支持血小板输注的需要，在极端情况下可消除 血小板作为一种可行的治疗方法，会导致出血的发病率和/或死亡率。抗人类白细胞抗原同种异体抗体 也可能是移植的重大障碍，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了，会导致排斥反应动力学和/或严重程度的增加。多胎雌性 特别容易发生同种免疫--怀孕似乎是随后进行同种免疫的最佳时机 血小板输注。因此，在许多情况下，对人类白细胞抗原的同种免疫是一个严重的问题。虽然 血小板的白细胞减少降低了同种异体免疫率，残留免疫力仍然很强。 重要的是，有挑衅性的数据表明，不同的白细胞亚群对免疫的影响是不同的(一些 促进豁免权和其他压制)。因此，大量去除白细胞可以消除抑制 (以及免疫接种)人群。详细了解不同白细胞的差异效应 子集将允许对血小板单位进行更复杂的工程，以进行选择性修饰 白细胞组合物，如果免疫亚群可以去除，抑制亚群可以保留。是这样的 在血小板输注以外的细胞治疗中，信息也可能非常有用。这 Proposal利用了一种创新的、新颖的和易驯服的小鼠模型，允许对 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反应方面存在协同作用； 对同一同种异体抗原的同种异体免疫根据不匹配的上下文而不同，从而打开了 个性化时代输血和移植的复杂配型/错配策略 医药。我们还发现，在老鼠身上，就像在人类身上一样，随后怀孕的起点增加了 对输血的同种异体免疫反应率。我们提出了两个具体的目标，重点是细胞机制 在幼稚受者和妊娠准备受者中对不同白细胞亚群的同种免疫反应， 分别进行了分析。我们在这一方法中进一步分析了不匹配的背景如何改变 给定同种异体抗原的免疫原性，以扩展我们最初的发现。为此生成的模型 建议在小鼠体内使用自然产生的MHC同种异体抗原，但重点放在特定的同种异体抗原上 EDGE工具可用于对同种异体反应性CD4+T细胞生物学和 同种异体抗体生成。总的来说，拟议的研究结合了新的工具和创新的假设，以 在PLT输注和细胞疗法的背景下，提出与同种异体免疫相关的机械性问题。