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: 10199012
• 负责人: Rachael Peretz Jackman
• 金额: $ 76.04万
• 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/10199012
• 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.

项目摘要/摘要 该项目的长期目标是确定哪些人有发展的风险 对血小板输血的临床有意义的同种抗体，以及为什么使目标干预措施减少 这些风险。靶向供体MHC抗原的同种异体免疫性是血小板输血的常见结果 并可能造成严重伤害，包括拒绝将来的输血或移植物。测量 血小板受体中抗MHC抗体的发生率差异很大，范围为7-55％。许多因素可以 影响同种免疫结果，但是一个较少的研究领域是收件人的基础的影响 健康。大多数需要输血的疾病和医疗干预措施具有深刻的 对遇到输血供体抗原的免疫学环境的影响。努力 评估患者健康对同种免疫化的作用受到限制，因为不同的患者组是 用不同类型和数量的血液产品治疗。 在这里，我们建议确定不同形式的免疫调节，在输血中很常见 接受者，影响外国MHC的同种异风。已建立的输血诱导的鼠模型 将对MHC的同种异体免疫将用于隔离受控和标准化的受体健康的作用 状况。中心假设是，由健康的免疫学环境建立 接收者对抗MHC抗体反应的大小和质量都有很大的影响 B细胞分化和T细胞帮助的差异驱动的同种异体输血。具体目的是 在同种异体输血时评估炎症或免疫抑制疗法的影响1） 同种对MHC抗原的反应，分类B细胞的激活和耐用的发展 免疫; 2）免疫学环境和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。 包括三种模型干预措施：化学疗法（癌症治疗），LPS（细菌感染）和 聚（I：C）（病毒感染）。对I类和II类MHC的抗体将通过同种型测量 使用我们既定的测定法。通过使用MHC四聚体，罕见的内源性MHC特异性B细胞 在定义的生理学下，将在野生型（非转基因/敲除）小鼠中检查种群 状况。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在血小板模型中驱动排斥的能力来评估 折射率和骨髓移植。这项工作将确定输血接收者的类 开发临床上有意义的抗MHC抗体的最大风险，以及驱动这些抗体的机制 回答将为未来的输血实践和新疗法的发展提供依据。