Platelet Transfusion Induced Transplant Rejection Across mHA barriers.

血小板输注诱导跨 mHA 屏障的移植排斥。

基本信息

批准号：
8529168
负责人：
JAMES C. ZIMRING
金额：
$ 22.8万
依托单位：
BLOODWORKS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8529168
关键词：
Activation Analysis Address Adverse effects Affect Anemia Animal Model Antibodies Antibody Formation Antigen-Presenting Cells Antigens Antithymoglobulin Aplastic Anemia B-Cell Activation Blood Blood Platelets Blood Transfusion Bone Marrow Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8B1 gene Cancer Patient Cancerous Cells Chronic Cooley&apos s anemia Data Development Diamond-Blackfan anemia Disease Dissection Dose Dysmyelopoietic Syndromes Engineering Environment Family Physicians Fanconi&apos s Anemia Fractionation Genetic Genetic Variation Graft Rejection Grant Helper-Inducer T-Lymphocyte Hematological Disease Hematopoiesis Hematopoietic Hemoglobinopathies Hemorrhage Histocompatibility Antigens Human Immune Immune response Immunity Immunization Individual International Iron Overload Lead Leukocytes MHC Class I Genes Malignant Neoplasms Minor Minor Histocompatibility Antigens Modeling Morbidity - disease rate Mus Mutation Neoplasms Non-Malignant Pancytopenia Pathway interactions Patients Peptides Physiological Platelet Count measurement Platelet Transfusion Play Procedures Property Proteins Publishing Regimen Relative (related person)Reporting Risk Role Sickle Cell Anemia Source Syndrome System T cell response T-Lymphocyte Techniques Testing Thalassemia Therapeutic Toxin Transfusion Transplantation United States base beta Thalassemia blood product conditioning design experience fludarabine immunogenicity in vivo irradiation killings mortality neoplastic cell novel strategies patient population peripheral blood prevent research study response selective expression transplant registry

项目摘要

DESCRIPTION (provided by applicant): Platelet transfusions are a common therapeutic maneuver for a variety of diseases that result in low platelet counts, which can lead to bleeding complications. A substantial number of transfused patients require platelets due to non-malignant hematopoietic disorders (either bone marrow failure syndromes or genetic defects in hematopoiesis), the only cure for which is bone marrow transplants (BMT). It has been observed that transfused patients have higher rates of BMT rejection, thus limiting the feasibility of utilizing BMT as a cure. A number of explanations for the increased rejection rates have been suggested, including immunological effects. We have recently reported in an animal model, that platelet transfusions in of themselves immunize against transplantation antigens that can then cause subsequent BMT rejection. Since BMT in this setting is MHC matched, these antigens are minor histocompatibility antigens (mHAs). Previously, it has been assumed that contaminating leukocytes in blood transfusions were the main source of immunization to minor antigens. However, the implementation of stringently leukoreduced blood products (fewer than 1x106 total leukocytes per unit of blood) has not decreased the rate of BMT rejection in chronically transfused patients. Based upon these findings, we hypothesized that non-leukocyte components are responsible for immunization against mHAs, and in this case, the platelets themselves. To address this hypothesis, and to closely model human transfusion, we have developed procedures to isolate and filter leukoreduce murine platelets using the same techniques and filters as are used in humans. Our data demonstrate that stringently filter leukoreduced platelets still induce BMT rejection. In support of this concept, we present data in this application to indicate that mHAs on transfused platelets are crosspresented into the MHC class I pathway of recipient antigen presenting cells (APCs), resulting in activation and expansion of recipient CD8+ T cells specific for the mHAs. Avoiding immunization by avoiding transfusion is not feasible, as the transfused platelets fulfill a therapeutic necessity; thus, generating strategies to circumvent the immune barriers will be required. The rational development of new approaches to avoid immunization requires a more detailed mechanistic understanding of the immunization and subsequent transplant rejection that are caused by platelet transfusion. We propose to study the mechanisms of platelet transfusion induced BMT rejection through the following specific aims. Specific Aim 1: Elucidate the immune mechanisms of PLT transfusion-induced BMT rejection. Specific Aim 2: Analysis of CD4+ T and CD8+ T cell immunization by mHAs carried by transfused PLTs. Specific Aim 3: Differential immunogenicity of distinct cell subsets in transfused blood. Together, the proposed aims will provide a mechanistic elucidation of how platelet transfusion induces subsequent BMT rejection. These studies have the potential to directly benefit patient populations who require platelet transfusions and subsequent BMT.

描述（由申请人提供）：血小板输注是治疗多种导致血小板计数低的疾病的常见治疗方法，血小板计数低可能导致出血并发症。大量输血患者因非恶性造血障碍（骨髓衰竭综合征或造血遗传缺陷）而需要血小板，唯一的治疗方法是骨髓移植（BMT）。据观察，输血患者的 BMT 排斥率较高，因此限制了利用 BMT 进行治疗的可行性。人们对排斥率增加提出了多种解释，包括免疫学效应。我们最近在动物模型中报道，血小板输注本身可以针对移植抗原产生免疫，从而导致随后的 BMT 排斥。由于这种情况下的 BMT 与 MHC 相匹配，因此这些抗原是次要组织相容性抗原 (mHA)。以前，人们认为输血中的污染白细胞是次要抗原免疫的主要来源。然而，严格降低白细胞含量的血液制品（每单位血液中白细胞总数低于1x106）的实施并没有降低长期输血患者的BMT排斥率。基于这些发现，我们假设非白细胞成分负责针对 mHA 的免疫，在这种情况下，是血小板本身。为了解决这一假设，并密切模拟人类输血，我们开发了使用与人类相同的技术和过滤器来分离和过滤白细胞减少小鼠血小板的程序。我们的数据表明，严格过滤白细胞减少的血小板仍然会引起 BMT 排斥。为了支持这一概念，我们在本申请中提供的数据表明，输注血小板上的 mHA 交叉呈递到受体抗原呈递细胞 (APC) 的 MHC I 类途径中，导致对 mHA 具有特异性的受体 CD8+ T 细胞的激活和扩增。通过避免输血来避免免疫是不可行的，因为输注的血小板满足治疗的需要；因此，需要制定规避免疫屏障的策略。合理开发避免免疫的新方法需要对血小板输注引起的免疫和随后的移植排斥有更详细的机制了解。我们建议通过以下具体目标来研究血小板输注引起 BMT 排斥的机制。具体目标1：阐明PLT输注引起BMT排斥的免疫机制。具体目标 2：分析输注 PLT 携带的 mHA 对 CD4+ T 和 CD8+ T 细胞的免疫作用。具体目标 3：输血中不同细胞亚群的差异免疫原性。总之，所提出的目标将从机制上阐明血小板输注如何诱导随后的 BMT 排斥。这些研究有可能直接使需要血小板输注和随后的 BMT 的患者群体受益。