Immunobiology of Alloimmunization by Platelet Transfusion

血小板输注同种免疫的免疫生物学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要对于许多导致血小板减少症的疾病，输注血小板是一种重要的维持生命的疗法。然而，血小板输注也可导致体液同种免疫，主要针对人类白细胞通过对多种同种异体抗原进行免疫，患者可能会对血小板产生耐药性。输血，导致难以支持血小板输注需求，在极端情况下可以消除血小板作为一种可行的疗法，导致抗 HLA 同种抗体导致发病和/或死亡。也可能成为移植的重大障碍，在某些情况下使患者没有资格进行移植，或如果它们确实被移植，会导致多妊娠雌性排斥反应的动力学和/或严重程度增加。特别容易发生同种异体免疫——怀孕似乎为随后的同种异体免疫做好了准备因此，HLA 的同种免疫在许多情况下都是一个重要问题。血小板白细胞减少降低了同种免疫率，但残余免疫力仍然很高。重要的是，有令人兴奋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消除抑制。（以及免疫）群体的详细了解不同白细胞的差异效应。子集将允许在选择性修饰方面对血小板单元进行更复杂的工程白细胞组成，如果可以去除免疫亚群并保留抑制亚群的话。该信息在血小板输注之外的细胞疗法中也可能具有很大的用途。该提案利用了一种创新、新颖且易于处理的小鼠模型，可以对不同白细胞相对亚群对同种免疫的贡献我们已经使用这个平台来进行。观察到 MHC 同种抗原之间在诱导免疫反应方面存在协同作用；对相同同种抗原的同种免疫根据不匹配的情况而有所不同，这为个性化时代输血和移植的复杂匹配/错配策略我们还发现，在小鼠中，就像在人类中一样，怀孕是随后增加的诱因。我们提出了两个具体目标，重点关注细胞机制。幼稚受者和妊娠引发受者对不同白细胞亚群的同种免疫反应，我们在这种方法中分别内置了对不匹配上下文如何变化的进一步分析。给定同种异体抗原的免疫原性，以扩展我们为此生成的模型。建议使用小鼠体内天然存在的 MHC 同种抗原，但重点关注切割的特定同种抗原边缘工具可用于对同种异体反应性 CD4+ T 细胞生物学和总的来说，拟议的研究将新颖的工具与创新的假设结合起来在 PLT 输注和细胞治疗的背景下提出与同种免疫相关的机制问题。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

在子宫内暴露于同种异体抗原引发小鼠对血小板输注的同种免疫。

DOI：
发表时间：
2021-03
期刊：
影响因子：
2.9
作者：
Poston, Jacqueline N;Jash, Arijita;Hannan, Lindsay M;Hay, Ariel M;Usaneerungrueng, Chomkan;Howie, Heather L;Kapp, Linda M;Zimring, James C
通讯作者：
Zimring, James C