B CELL TRANSFUSIONS FOR POSTBMT IMMUNE DEFICIENCY

描述：(申请者摘要)申请者的总体目标是 降低长期骨髓感染性疾病的发病率和死亡率 移植幸存者，同时，提供对 免疫记忆生理学。应用程序的部分导致 临床结果：接受骨髓移植的患者 移植后至少一年免疫缺陷，部分原因是 缺乏B细胞。申请人希望尝试改进这些 通过向患者提供来自其自身的B细胞来提高体液免疫能力 骨髓捐献者在移植后一到两个月。这项工作是分工完成的 分4个步骤：(1)研究B细胞的大规模分离 献血者。(2)确保受血者输血的安全性 B细胞。(3)进行试点前瞻性随机试验，比较 B细胞输注患者与对照组患者对疫苗的反应性。 (4)如果试点结果令人鼓舞，则进行最终的大规模 一项前瞻性随机试验，比较患者数量和严重程度 B细胞输注患者与对照组患者的感染情况。在这 应用程序，仅请求对第(1)-(3)步提供支持。这一部分 导致免疫学信息的应用程序：该应用程序 还试图确定(A)幼稚和幼稚的大致寿命 人类输注后的记忆B细胞克隆，以及(B) 长期抗体产生是否是周期性分化所致 B细胞转化为浆细胞或由于浆细胞寿命长所致。(A)至 定义原始B细胞克隆和记忆B细胞克隆的大致寿命， 幼稚B细胞和记忆B细胞数量的连续测量将是 在输注B细胞的患者和对照组患者中都进行了检测。这个 特定B细胞亚群的寿命越长，就越长 输血后B细胞输注患者应具有较高的 将这一亚群的血液计数与对照组进行比较。因此， 从输注B细胞到最后一个时间点的时间段 检测到明显更高的幼稚或记忆性B细胞计数 输注B细胞的患者与对照组的患者将被称为 原始B细胞克隆或记忆B细胞克隆的大致寿命。(B)在 同时，患者将被用来了解是否长期 产生抗体以召回天花病毒等抗原 通过天花特异的B细胞介导，其中一些细胞周期性地 分化为浆细胞或通过长天花特异的血浆 细胞。与对照组相比，输注B细胞的患者 接受了更多的B细胞，但相同数量的血浆 细胞。因此，如果在B细胞输注几个月后 B细胞输血患者血清天花抗体水平较高， 假设是B细胞而不是长寿的浆细胞 负责长期生产免疫球蛋白，反之亦然。

DESCRIPTION: (Applicant's Abstract) The applicant's broad objective is to decrease the infectious morbidity and mortality of long-term marrow transplant survivors and, at the same time, to provide insight into the physiology of immune memory. The part of the application leading to clinical outcome: Patients undergoing bone marrow transplantation are immunodeficient for at least one year after grafting due in part to the lack of B cells. The applicant desires to attempt to improve these patients' humoral immunity by providing them with B cells from their marrow donors at one to two months after grafting. The work is divided into 4 steps: (1) Work out the large scale separation of B cells from donor blood. (2) Establish the safety of transfusions of the enriched B cells. (3) Perform a pilot prospective randomized trial comparing the responsiveness to vaccines in B cell-transfused vs. control patients. (4) If the pilot results are encouraging, perform a definitive large prospective randomized trial comparing the number and severity of infections in B cell-transfused vs. control patients. In this application, support is requested only for steps (1)-(3). The part of the application leading to immunologic information: This application also seeks to determine (A) the approximate life span of naive and memory B cell clones following infusion into human beings, and (B) whether long-term antibody production is due to periodic differentiation of B cells into plasma cells or due to long-lived plasma cells. (A) To define the approximate life span of naive and memory B cell clones, serial measurements of the mounts of naive and memory B cells will be performed in both the B cell-transfused and control patients. The longer the life span of a particular B cell subpopulation, the longer after the transfusions should the B cell transfused patients have higher blood counts of this subpopulation compared to the controls. Therefore, the time period from transfusing B cells to the last time point at which significantly higher naive or memory B cell counts are detected in the B cell-transfused vs. the control patients will be called the approximate life span of the naive or memory B cell clones. (B) At the same time, the patients will be used to find out whether the long-term production of antibodies to recall antigens like smallpox virus is mediated through smallpox-specific B cells some of which periodically differentiate into plasma cells or by long smallpox-specific plasma cells. Compared to the controls, the B cell transfused patients will have received substantially more B cells but the same amount of plasma cells. Therefore, if several months after the B cell transfusion the B cell transfused patients have higher serum levels of smallpox IgG, it will be assumed that B cells rather than long lived plasma cells are responsible for the long term IgG production, and vice versa.