The impact of illness and medical treatments on the alloantibody response to platelet transfusion

疾病和药物治疗对血小板输注同种抗体反应的影响

• 批准号: 9980477
• 负责人: Rachael Peretz Jackman
• 金额: $ 76.49万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980477
• 关键词: Ablation; Acute Lung Injury; Allogenic; Alloimmunization; Antibodies; Antibody Response; Antigens; Area; Automobile Driving; B cell differentiation; B-Cell Activation; B-Cell Development; B-Lymphocytes; Bacterial Infections; Biological Assay; Blood; Blood Platelets; Blood Transfusion; Bone Marrow Transplantation; Cells; Clinical; Development; Engraftment; Environment; Future; Genetic; Goals; Health; Hematopoietic Stem Cell Transplantation; Histocompatibility; Histocompatibility Antigens; Homeostasis; Illness impact; Immune; Immune system; Immunity; Immunoglobulin Class Switching; Immunologics; Immunomodulators; Immunosuppression; Incidence; Individual; Infection; Inflammation; Inflammatory; Intervention; Isoantibodies; Knockout Mice; Knowledge; Leukocytes; Lymphocyte; Measurement; Measures; Mediating; Medical; Memory B-Lymphocyte; Modeling; Organ; Outcome; Patients; Pattern; Peripheral; Phenotype; Physiological; Plasma; Plasma Cells; Platelet Transfusion; Poly I-C; Population; Production; Refractory; Risk; Role; Sampling; Secondary to; Serum; Severities; Shapes; Side; Signal Transduction; Solid; Standardization; Stem cell transplant; T cell differentiation; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Titrations; Transfusion; Transplantation; Virus Diseases; Work; blood product; blood treatment; cancer therapy; chemotherapy; clinical development; clinically significant; cytokine; functional outcomes; genetic risk factor; immune function; immunogenicity; immunoregulation; insight; mouse model; novel therapeutics; pathogen; patient population; prevent; response; time use

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to determine which individuals are at greatest risk of developing clinically meaningful alloantibodies to platelet transfusion, and why, to enable targeted interventions to reduce these risks. Alloimmunization targeting donor MHC antigens is a common consequence of platelet transfusion and can cause serious harm including rejection of future transfusions or transplants. Measurements of the incidence of anti-MHC antibodies in platelet recipients vary widely, ranging from 7-55%. Many factors can influence alloimmunization outcomes, but one less studied area is the influence of the recipient's underlying health. The majority of the illnesses and medical interventions that necessitate transfusion have a profound impact on the immunological environment in which transfused donor antigens are encountered. Efforts to evaluate the role of patient health on alloimmunization have been limited as different groups of patients are treated with varying types and amounts of blood products. Here we propose to determine how different forms of immune modulation, common among transfusion recipients, influence the alloresponse to foreign MHC. An established murine model of transfusion-induced alloimmunization to MHC will be used to isolate the role of recipient health under controlled and standardized conditions. The central hypothesis is that the immunological environment established by the health of the recipient has a strong impact on both the magnitude and quality of the anti-MHC antibody response to allogeneic transfusion, driven by differences in B cell differentiation and T cell help. The specific aims are to evaluate the impact of inflammation or immunosuppressive therapies at the time of allogeneic transfusion on 1) alloantibody responses to MHC antigens, activation of allospecific B cells and the development of durable immunity; 2) the immunological environment and the quality of T cell help; and 3) the clinical significance and functional capabilities of alloantibodies generated under these different inflammatory or suppressive conditions. Three model interventions are included: chemotherapy (cancer treatment), LPS (bacterial infection), and poly(I:C) (viral infection). Antibodies against class I and class II MHC will be measured by isotype over time using our established assays. Through the use of MHC-tetramers, rare endogenous MHC-specific B cell populations will be examined in wild-type (non-transgenic/knock-out) mice under defined physiological conditions. Impact on cytokine milieu, T cell differentiation, and lymphocyte homeostasis will be determined. The clinical significance of alloantibodies will be assessed by their ability to drive rejection in models of platelet refractoriness and bone marrow transplantation. This work will identify classes of transfusion recipients at greatest risk for development of clinically meaningful anti-MHC antibodies, and the mechanisms driving these responses, which will inform future transfusion practice and development of new therapeutics.

项目总结/摘要 该项目的长期目标是确定哪些人最有可能发展为 血小板输注的具有临床意义的同种抗体，以及原因，以使有针对性的干预措施，以减少 这些风险。针对供体MHC抗原的同种免疫是血小板输注的常见结果 并且可能导致严重的伤害，包括排斥未来的输血或移植。测量 血小板接受者中抗MHC抗体的发生率变化很大，范围为7- 55%。许多因素可以 影响同种免疫结果，但一个研究较少的领域是受者的潜在影响。 健康大多数需要输血的疾病和医疗干预都有深刻的影响。 对遇到输注供体抗原的免疫环境的影响。努力 评估患者健康对同种免疫的作用有限，因为不同的患者群体 用不同类型和数量的血液制品治疗。 在这里，我们建议确定如何不同形式的免疫调节，常见的输血 受体，影响对外源MHC的同种异体反应。建立输血诱导的小鼠模型， MHC的同种免疫将用于在受控和标准化的条件下隔离受体健康的作用。 条件中心假设是，由健康的人建立的免疫环境， 受体对抗MHC抗体应答的幅度和质量都有很大的影响， 同种异体输血，由B细胞分化和T细胞帮助的差异驱动。具体目标是 评价同种异体输血时炎症或免疫抑制治疗对1） 同种抗体对MHC抗原的应答、同种特异性B细胞的活化和持久免疫应答的发生， 免疫; 2）免疫环境和T细胞帮助的质量; 3）临床意义和 在这些不同的炎症或抑制条件下产生的同种抗体的功能能力。 包括三种模型干预：化疗（癌症治疗），LPS（细菌感染）， poly（I：C）（病毒感染）。将通过同种型随时间推移测量针对I类和II类MHC的抗体 使用我们已建立的检测方法。通过使用MHC四聚体，罕见的内源性MHC特异性B细胞 将在限定的生理条件下在野生型（非转基因/敲除）小鼠中检查群体。 条件将确定对细胞因子环境、T细胞分化和淋巴细胞稳态的影响。 同种抗体的临床意义将通过其在血小板模型中驱动排斥反应的能力来评估。 难治性和骨髓移植。这项工作将确定输血接受者的类别， 产生具有临床意义的抗MHC抗体的最大风险，以及驱动这些抗体的机制 反应，这将为未来的输血实践和新疗法的开发提供信息。