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

项目摘要/摘要 这个项目的长期目标是确定哪些人患癌症的风险最大。 临床上有意义的血小板输注同种异体抗体，以及为什么，使有针对性的干预能够减少 这些风险。针对供体MHC抗原的同种异体免疫是血小板输注的常见后果 并可能造成严重的伤害，包括对未来的输血或移植产生排斥反应。测量的结果 抗MHC抗体在血小板接受者中的发生率差异很大，从7%到55%不等。很多因素都可以 影响异基因免疫结果，但一个较少研究的领域是接受者潜在的影响 健康。大多数需要输血的疾病和医疗干预都有深远的影响 对遇到输血供体抗原的免疫环境的影响。努力实现 评估患者健康在异体免疫中的作用受到限制，因为不同的患者群体 使用不同类型和数量的血液产品进行治疗。 在这里，我们建议确定不同形式的免疫调节，在输血中普遍存在 受体影响对外来MHC的同种异体反应。一种已建立的小鼠输血诱导模型 将使用对MHC的同种免疫来隔离受者健康在受控和标准化下的作用 条件。中心假设是由人的健康所建立的免疫环境 受体对抗MHC抗体应答的大小和质量都有很大影响 异体输血，在B细胞分化和T细胞分化的推动下有所帮助。具体目标是 评估异体输血时炎症或免疫抑制治疗对1)的影响 同种异体抗体对MHC抗原的反应、同种异体特异性B细胞的激活和耐受性的发展 2)免疫环境和T细胞质量的帮助；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异体抗体的功能。 包括三种模式干预：化疗(癌症治疗)、内毒素(细菌感染)和 Poly(I：C)(病毒感染)。随着时间的推移，针对I类和II类MHC的抗体将通过同型进行测定。 使用我们已建立的化验方法。通过使用MHC-四聚体，罕见的内源性MHC特异性B细胞 野生型(非转基因/基因敲除)小鼠的种群将在定义的生理条件下进行检查 条件。对细胞因子环境、T细胞分化和淋巴细胞动态平衡的影响将被确定。 同种抗体的临床意义将通过它们在血小板模型中驱动排斥反应的能力来评估。 难治性与骨髓移植。这项工作将确定输血接受者的类别 发生具有临床意义的抗MHC抗体的最大风险及其驱动机制 这将为今后的输血实践和新疗法的发展提供信息。

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.