Platelet Transfusion Induced Transplant Rejection Across mHA barriers.

血小板输注是导致血小板减少的各种疾病的常用治疗方法。 这可能会导致出血并发症。相当数量的输血患者需要血小板。 由于非恶性造血疾病(无论是骨髓衰竭综合征或遗传缺陷 骨髓移植(BMT)是唯一的治疗方法。据观察， 输血患者的骨髓移植排斥反应发生率较高，因此限制了使用骨髓移植作为治疗方法的可行性。 对于排斥率的增加，已经提出了一些解释，包括免疫学上的 效果。我们最近在一个动物模型中报道，血小板输注本身就能免疫 抗移植抗原，然后可能导致随后的骨髓移植排斥反应。由于此设置中的BMT为 MHC匹配，这些抗原是次要组织相容抗原(MHAS)。此前，人们一直认为 输血中污染的白细胞是对次要抗原免疫的主要来源。 然而，实施严格的降白细胞血液产品(每小时白细胞总数少于1x106) 单位血)并不能降低长期输血患者的骨髓移植排斥反应的发生率。基于 这些发现，我们假设非白细胞成分负责免疫针对 在这种情况下，是指血小板本身。为了解决这一假设，并密切模拟人类 输血，我们已经开发了分离和过滤白细胞减少小鼠血小板使用相同的程序 人类使用的技术和过滤器。我们的数据表明，严格过滤可以减少白细胞 血小板仍然会引起骨髓移植排斥反应。为了支持这一概念，我们在此应用程序中提供数据以表明 输注的血小板上的mhA被交叉传递到受体抗原的MHC-I类途径。 提呈细胞(APC)，导致MHAs特异性受体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，因为输注的血小板完成了一种治疗 这是必要的；因此，需要制定策略绕过免疫屏障。理性的人 开发避免免疫的新方法需要从机制上更详细地了解 血小板输注引起的免疫和随后的移植排斥反应。我们建议 从以下几个方面研究血小板输注诱导骨髓移植排斥反应的机制。 具体目的1：阐明PLT输注诱导骨髓移植排斥反应的免疫机制。 特异性目的2：分析输注的PLT携带的mHAS对CD4+T细胞和CD8+T细胞的免疫效果。 具体目标3：输血中不同细胞亚群的不同免疫原性。 综上所述，提出的目标将为血小板输注如何诱导 随后的BMT拒绝。这些研究有可能直接造福于那些需要 血小板输注和随后的骨髓移植。

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 has 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 require 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.