ALTERNATE MARROW DONORS

替代骨髓捐赠者

• 批准号: 6217282
• 负责人: John Andrew Hansen
• 金额: $ 34.64万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217282
• 关键词: CD34 molecule; CD4 molecule; CD8 molecule; MHC class II antigen; acute leukemia; alleles; bone marrow transplantation; clinical research; clinical trials; family genetics; gene expression; graft versus host disease; hematopoietic stem cells; histocompatibility typing; human morbidity; human mortality; human subject; human therapy evaluation; immunosuppression; major histocompatibility complex; monoclonal antibody; neoplasm /cancer immunotherapy; polymerase chain reaction; transplant rejection; transplantation resource /registry /referral center

The goal of this project is to increase access to normal donor hematopoietic stem cell transplants for patients who lack an HLA- identical sibling donor, and to improve the safety and efficacy of these transplants as therapy for patients with hematological malignancy. Transplants from alternative donors with variable and sometimes undetected HLA mismatching have a higher risk of morbidity and transplant-related mortality (TRM) due to more severe graft- versus-host-disease (GVHD) than HLA identical sibling transplants. Studies outlined in the four specific aims of this project are directed to improving methods and criteria for donor matching, reducing GVHD and TRM, and understanding the nature of the prolonged immune deficiency that frequently occurs in HLA mismatched and unrelated donor transplants. Advances in DNA-based typing technology has allowed us to identify previously unrecognized HLA genetic variations that occur between patients and their haploidentical or unrelated donor. In the studies proposed here we will determine the degree of mismatching for HLA-A,B,C,DQ and DP alleles that can be safely tolerated without significantly increasing the risk of severe GVHD, and we will better define the situations where HLA mismatching and the potential for a stronger graft-versus-leukemia (GVL) effect may be beneficial. A clinical trail will be undertaken to determine if TRM might be reduced by improving the rate and quality of engraftment using growth factor-mobilized peripheral blood stem cells (PBSC). New methods for selected T-cell depletion (TCD) of HLA mismatched marrow or PBSC grafts from haploidentical related and unrelated donors will be examined to determine if this approach to GVHD prevention will allow us to safely undertake these kind of transplants for patients unable to find an optimal HLA match. Laboratory studies are proposed to examine the kinetics and diversity of posttransplant T- cell reconstitution especially in patients receiving TCD stem cell grafts by analyzing the expression of T-cell receptor (TCR) VB gene families using reverse-transcriptase (RT) and the polymerase chain reaction (PCR) to amplify individual TCR transcripts. The size variation of the CDR3 region of the TCR encoded by recombinant VDJ segments will be analyzed by spectratyping to identify individual TCR clonotypes as a means for estimating clonal diversity and identifying host-reactive T- cell clones that may be involved in GVHD. This method may provide an objective means for monitoring the effectiveness of immunosuppression therapy in the prevention and treatment of GVHD, and may help determine when tolerance has occurred and patients can be safely withdrawn from immunosuppression therapy.

该项目的目的是增加对普通捐助者的访问 缺乏HLA-的患者的造血干细胞移植 相同的兄弟姐妹供体，并提高 这些移植作为血液学患者的治疗 恶性。 来自替代捐赠者的移植，可变和 有时未发现的HLA不匹配具有更高的发病风险 由于更严重的移植物而导致的与移植相关的死亡率（TRM） 与HLA相同的兄弟式移植物相比，与宿主疾病相比（GVHD）。 该项目的四个具体目标中概述的研究是指向的 改善捐助者匹配的方法和标准，减少GVHD 和TRM，并了解长期免疫的性质 在HLA不匹配和无关的HLA中经常出现的不足 供体移植。 基于DNA的打字技术的进步具有 允许我们识别以前未被认可的HLA遗传变异 这发生在患者及其单倍体或无关的 捐助者。 在这里提出的研究中，我们将确定 对HLA-A，B，C，DQ和DP等位基因的不匹配，可以安全 宽容而没有显着增加严重GVHD的风险，并且 我们将更好地定义HLA不匹配和 可能会产生更强的移植物 - 白血病（GVL）效应 有利。 将进行临床路线以确定是否trm 通过提高植入的速度和质量可以降低 使用生长因子验证的外周血干细胞（PBSC）。 新的 HLA不匹配的骨髓的选定T细胞耗竭（TCD）的方法 或来自单倍性相关和无关捐助者的PBSC移植物 进行检查以确定这种预防GVHD的方法是否会 允许我们安全地为患者进行此类移植 找不到最佳的HLA匹配。 实验室研究是 提议检查移植后T-的动力学和多样性 细胞重建，尤其是在接受TCD干细胞移植的患者中 通过分析T细胞受体（TCR）Vb基因家族的表达 使用反向转移酶（RT）和聚合酶链反应 （PCR）放大单个TCR转录本。 大小变化 由重组VDJ段编码的TCR的CDR3区域将是 通过频谱分析以识别单个TCR clonotypes作为A 估计克隆多样性和识别宿主反应性T-的手段 可能涉及GVHD的细胞克隆。 此方法可能会提供 监视有效性的客观手段 预防和治疗GVHD的免疫抑制疗法， 并可能有助于确定何时发生公差，并且患者可以 安全地退出免疫抑制疗法。