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）：血小板输血是多种疾病的常见治疗动作，导致血小板计数低，这可能导致出血并发症。由于非恶性造血疾病（造血综合症或造血性遗传缺陷），大量的输血患者需要血小板，这是唯一的治疗方法是骨髓移植剂（BMT）。已经观察到，输血患者的BMT排斥率较高，因此限制了利用BMT作为治愈的可行性。已经提出了一些对拒绝率提高的解释，包括免疫学影响。我们最近在动物模型中报道了血小板输血本身会免疫反对移植抗原，然后会导致随后的BMT排斥反应。由于在这种情况下BMT与MHC匹配，因此这些抗原是较小的组织相容性抗原（MHA）。以前，已经假定输血中污染的白细胞是对次要抗原免疫的主要来源。然而，实施严格的白细胞血液产物（每单位血液的总白细胞总数少于1x106总白细胞）并未降低长期输卵患者的BMT排斥率。基于这些发现，我们假设非白细胞成分负责对MHA的免疫接种，在这种情况下，血小板本身。为了解决这一假设，为了对人类的输血进行密切的模型，我们开发了使用与人类使用的相同技术和过滤器分离和过滤leukoreduce鼠血小板的程序。我们的数据表明，严格过滤白细胞的血小板仍会引起BMT排斥。为了支持此概念，我们在本应用程序中介绍了数据，以表明输血血小板上的MHA被交叉代表到受体抗原呈现细胞（APC）的MHC I类途径（APC），从而导致受体CD8+ T细胞的激活和扩展。避免通过输血来避免免疫是不可行的，因为输血的血小板满足了治疗性的必要性；因此，将需要生成规避免疫屏障的策略。避免免疫的新方法的合理发展需要对血小板输血引起的免疫和随后的移植排斥的更详细的机械理解。我们建议通过以下特定目的研究血小板输血的机制。具体目标1：阐明PLT输血诱导的BMT排斥反应的免疫机制。具体目标2：通过输血PLT携带的MHA对CD4+ T和CD8+ T细胞免疫的分析。特定目的3：输血血液中不同细胞亚群的差异免疫原性。拟议的目标共同提供了一种机械阐明，即血小板输血如何诱导随后的BMT排斥反应。这些研究有可能直接使需要血小板输血和随后BMT的患者人群受益。