BIOLOGIC AND IMMUNOLOGIC ASPECTS OF TRANSFUSION MEDICINE

输血医学的生物学和免疫学方面

• 批准号: 7128161
• 负责人: Sherrill J. Slichter
• 金额: $ 197.33万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128161
• 关键词: clinical research

DESCRIPTION (provided by applicant): Our research focuses on several biologic and immunologic aspects of transfusion medicine. Three projects deal with questions related to platelet biology. Specifically, Dr. Slichter's project seeks to define the parameters that must be met to allow extension of platelet storage by evaluating the effects of an initial collection injury that may limit storage duration and the role of storage solutions in facilitating extended platelet storage. Dr. Gilligan and Reems' project expects to identify the optimal methods of growing megakaryocytes in culture with the goal of producing platelets or "platelet-like fragments" that function similarly to platelets in maintaining hemostasis. Dr. Josephson's project focuses on the development of foamy virus vectors as a gene transfer system to deliver therapeutic genes into hematopoietic stem cells. The target disease that he will use as a model for his system is congenital amegakaryocytic thrombocytopenia (CAMT). Two additional projects have an immunologic emphasis. Dr. Nelson's project involves transfusing three different types of blood products [standard (unmodified), leukoreduced, or leukoreduced gamma-irradiated] into immunocompetent patients undergoing open-heart surgery. The differences in serologic and cellular immune responses in the three patient cohorts as well as the influence of HLA Class II sharing between donors and recipients on immunologic outcomes will be evaluated. Dr. S. Pratt and Thompson's project addresses issues related to the prevention or reversal of inhibitor antibody formation in patients with acquired or congenital hemophilia A. Modification of T-cell epitopes in FVIII may lead to non-immunogenic FVIII replacement therapy while new peptides or recombinant proteins may be useful in tolerance induction for patients with existing antibodies. Finally, an administrative core will be used to maintain an interactive environment among the SCCOR scientists and provide administrative and statistical support. In summary, we have utilized the established expertise of our scientists to address several important questions in Transfusion Medicine. In addition, most projects involve the skills of one or more Blood Center scientists working within and between the projects to accomplish the objectives of this SCCOR Program. (End of Abstract) PROJECT 1: Strategies to Extend Platelet Storage (Slichter, Sherrill) DESCRIPTION (provided by applicant): The primary objective of these studies is to determine whether platelets (plts) can be stored for longer than the currently-licensed 5 days. Furthermore, does the duration of plt storage depend on the type of plt product being stored (apheresis plts, plt concentrates prepared from plt-rich plasma (PRP), or from buffy coats (BC), pre-storage pooled PRP plt concentrates, or pathogen-reduced apheresis or BC plts), and the medium used for storage; i.e., plasma or a storage solution. The four critical questions that will be addressed in our studies are: 1) does the method of plt collection using apheresis procedures versus preparing plt concentrates from whole blood influence storage duration?; 2) does pre-storage pooling of plt concentrates affect plt viability?; 3) do plt storage solutions allow plts to be stored longer than plts stored in plasma?; and 4) can pathogen-reduced plts be stored for extended time periods similar to non-pathogen reduced plts? Although in vitro tests will be performed to document post-storage plt counts as well as a variety of assays to determine post-storage plt function, metabolism and apoptosis, the post-storage quality of the extended stored plts will be based on in vivo measurements in normal volunteers and thrombocytopenic patients. Specifically, radiolabeled plt recovery and survival measurements of extended stored autologous plts in normal volunteers will be used to determine post-storage plt viability for all types of plt products stored in plasma versus a storage solution. For plts that are stored for longer than 8 days and/or are stored in a storage solution, transfusion studies in the thrombocytopenic patients will be used to evaluate plt viability by measuring the radiolabeled recovery and survival of the donors' plts following transfusion. Alternatively, patient responses to transfused donor plts will be determined by measuring post-transfusion plt increments, corrected count increments, and days-to-next transfusion. Plt function (i.e., hemostasis) following the transfusion of extended stored donor plts will be monitored by plt count versus bleeding time measurements and by radiochromium-labeled stool blood loss studies. At the conclusion of these studies, we should know how long each type of plts can be stored in plasma or Plasmalyte, the relative merits of each type of plts, and whether the extended stored plts are both viable and functional when given to thrombocytopenic patients. (End of Abstract)

描述（由申请人提供）： 我们的研究重点是输血医学的几个生物学和免疫学方面。 三个项目涉及与血小板生物学相关的问题。 具体来说，Slichter 博士的项目旨在通过评估可能限制储存持续时间的初始收集损伤的影响以及储存溶液在促进延长血小板储存中的作用来定义允许延长血小板储存所必须满足的参数。 Gilligan 博士和 Reems 的项目期望确定在培养物中培养巨核细胞的最佳方法，目的是产生血小板或“血小板样片段”，其功能与血小板在维持止血方面类似。约瑟夫森博士的项目重点是开发泡沫病毒载体作为基因转移系统，将治疗基因传递到造血干细胞中。他将用作其系统模型的目标疾病是先天性无巨核细胞血小板减少症 (CAMT)。另外两个项目强调免疫学。 尼尔森博士的项目涉及将三种不同类型的血液制品[标准（未改良）、去白细胞或经过伽马射线照射的去白细胞]输注到接受心脏直视手术的免疫功能正常的患者体内。 将评估三个患者队列中血清学和细胞免疫反应的差异以及供体和受体之间 HLA II 类共享对免疫结果的影响。 S. Pratt 博士和 Thompson 的项目解决了与获得性或先天性血友病 A 患者中预防或逆转抑制剂抗体形成相关的问题。FVIII 中 T 细胞表位的修饰可能会导致非免疫原性 FVIII 替代疗法，而新的肽或重组蛋白可能有助于诱导具有现有抗体的患者的耐受性。 最后，行政核心将用于维持 SCCOR 科学家之间的互动环境，并提供行政和统计支持。总之，我们利用科学家现有的专业知识来解决输血医学中的几个重要问题。 此外，大多数项目都涉及一名或多名血液中心科学家在项目内部和项目之间工作的技能，以实现该 SCCOR 计划的目标。 （摘要完） 项目 1：扩展血小板储存的策略 （谢里尔·斯利希特） 描述（由申请人提供）： 这些研究的主要目的是确定血小板 (plt) 的保存时间是否可以超过目前许可的 5 天。 此外，plt 储存的持续时间是否取决于所储存的 plt 产品的类型（单采 plt、从富含 plt 的血浆 (PRP) 或从血沉棕黄层 (BC) 制备的 plt 浓缩物、预储存混合的 PRP plt 浓缩物或减少病原体的单采术或 BC plts)，以及用于储存的培养基；即血浆或储存溶液。 我们的研究将解决的四个关键问题是：1）使用单采程序收集 PLT 的方法与从全血中制备 PLT 浓缩物相比是否会影响储存时间？ 2) PLT 浓缩物的预储存汇集是否会影响 PLT 活力？ 3) plt 储存溶液是否可以比血浆中保存的 plt 保存更长时间？ 4) 病原体减少的 plt 是否可以像非病原体减少的 plt 一样储存较长时间？ 尽管将进行体外测试来记录储存后的 plt 计数以及各种测定来确定储存后 plt 的功能、代谢和细胞凋亡，但长期储存的 plt 的储存后质量将基于体内测量在正常志愿者和血小板减少症患者中。 具体而言，将使用对正常志愿者中长期保存的自体 plt 的放射性标记 plt 回收率和存活率测量来确定血浆中保存的所有类型的 plt 产品相对于保存溶液的保存后 plt 活力。 对于保存超过 8 天和/或保存在保存溶液中的 plt，血小板减少症患者的输血研究将用于通过测量输血后供体 plt 的放射性标记恢复和存活来评估 plt 活力。或者，患者对输血供体 plt 的反应将通过测量输血后 plt 增量、校正计数增量和距下一次输血的天数来确定。 输注长期保存的供体 plt 后的 Plt 功能（即止血）将通过 plt 计数与出血时间测量以及放射性铬标记的粪便失血研究来监测。 在这些研究结束时，我们应该知道每种类型的 plts 在血浆或 Plasmalyte 中可以保存多长时间，每种类型的 plts 的相对优点，以及延长保存的 plts 在给予血小板减少症患者时是否具有活力和功能。 （摘要完）