TLI and ATG Conditioning for Combined Kidney and Blood Stem Cell Transplantation

TLI 和 ATG 调理肾和血液干细胞联合移植

• 批准号: 9288200
• 负责人: SAMUEL STROBER
• 金额: $ 53.54万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9288200
• 关键词: Adverse effects; Alloantigen; Antibodies; Antithymoglobulin; Autoimmune Diseases; Biological Assay; Blood; CD3 Antigens; CD34 gene; Cardiovascular system; Cell Transplants; Cells; Chimerism; Chronic; Clinical Research; Clonal Deletion; Clone Cells; Data; Databases; Dendritic Cells; Development; Dose; Enrollment; Equilibrium; Frequencies; Goals; Graft Rejection; Graft Survival; Grant; HLA Antigens; Haplotypes; Hematopoietic; Hematopoietic stem cells; High-Throughput Nucleotide Sequencing; Immune; Immunologic Monitoring; Immunosuppressive Agents; Immunotherapy; Infection; Inflammation; Inflammatory; Kidney; Kidney Transplantation; Leukocytes; Living Donors; Lymphatic Irradiation; Lymphoid Tissue; Malignant Neoplasms; Measures; Medical center; Monitor; Myelogenous; Nomograms; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Protocols documentation; Radiation; Registries; Research; Risk; Safety; Severe Adverse Event; Stem cell transplant; Suppressor-Effector T-Lymphocytes; T-Cell Receptor Genes; T-Lymphocyte; Testing; Tissues; Transplantation; Universities; Update; Urine; Wisconsin; conditioning; data registry; drug withdrawal; graft vs host disease; monocyte; patient stratification; prevent; standard of care; success; urinary

Project Summary/Abstract The goal of the proposed clinical study is to induce tolerance to combined kidney and hematopoietic cell transplants after conditioning with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) in patients given grafts from related living HLA haplotype matched donors or from unrelated living donors who are matched at 3 HLA antigens. Establishment of tolerance is expected to eliminate the usual lifelong need for immunosuppressive (IS) drugs and attendant side effects such that complete IS drug withdrawal will be accomplished without subsequent evidence of rejection. The proposed studies build upon our progress in the previous grant periods in the successful induction of chimerism and tolerance in about 80% of fully HLA matched patients, the ability to establish persistent high levels of mixed chimerism in related HLA haplotype matched patients, and the 100% kidney graft survival in 25 HLA matched and 20 HLA mismatched patients enrolled in the tolerance protocols during the past 15 years. We will test the hypothesis that high levels of mixed chimerism that persist for more than 1 year will be maintained during and after IS drug withdrawal, and result in tolerance. We hypothesize that tolerance will be predicted by evidence of alloreactive T cell clonal deletion measured by high throughput sequencing of TCR genes, lack of development of donor specific antibodies (DSA), and lack of inflammatory cell PCR products in the urine. The changes in the lymphoid tissues that promote tolerance after conditioning will be monitored by determining changes in the balance of effector T cells and immunosuppressive regulatory cells including monocytes and myeloid derived suppressor cells (MDSCs) in the blood. In order to assess the longterm outcome of patients, we propose to establish a registry of efficacy and risks for all patients enrolled in our tolerance protocols since inception for comparison to standard of care patients in our centers and in the national registry. In addition, we will perform longterm immune monitoring parameters to measure persistence of chimerism, donor specific unresponsiveness in the MLR, and the T cell clonal repertoire. In conclusion, we will attempt to induce tolerance, identify mechanisms and predictors such that IS drugs can be guided appropriately, and determine the durability of immune changes that underlie tolerance.

项目总结/摘要 拟进行的临床研究的目的是诱导对联合肾脏和造血细胞的耐受性 患者接受全淋巴照射（TLI）和抗胸腺细胞球蛋白（ATG）预处理后的移植 移植物来自相关的HLA单倍型匹配的活体供体或来自无关的活体供体， 3种HLA抗原匹配。建立耐受性有望消除通常的终身需要， 免疫抑制（IS）药物和伴随的副作用，如完全的IS药物戒断将是 在没有后续拒绝证据的情况下完成。建议的研究是建基于我们在 在以往的资助期内成功诱导嵌合和耐受的HLA完全符合率约为80% 匹配的患者，在相关HLA单倍型中建立持续高水平混合嵌合体的能力 25例HLA相合和20例HLA不相合患者移植肾存活率均为100 在过去的15年里参加了耐受性方案。我们将检验一个假设， 持续超过1年的混合嵌合体将在IS药物停药期间和停药后维持，以及 导致宽容。我们假设，耐受性将通过同种异体反应性T细胞克隆的证据来预测。 通过TCR基因的高通量测序测量的缺失，缺乏供体特异性PCR的开发， 抗体（DSA），以及尿液中缺乏炎性细胞PCR产物。淋巴细胞的变化 调节后促进耐受性的组织将通过测定 效应T细胞和免疫抑制调节细胞，包括单核细胞和髓源性抑制细胞 血液中的干细胞（MDSC）。为了评估患者的长期结果，我们建议建立一个 自开始以来入组耐受性方案的所有患者的疗效和风险登记， 我们中心和国家登记处的标准治疗患者。此外，我们将长期 免疫监测参数，以测量嵌合体的持续性，供体特异性无反应性， MLR和T细胞克隆库。总之，我们将尝试诱导耐受，确定机制， 和预测因子，以便IS药物可以得到适当的指导，并确定免疫的持久性。 宽容背后的变化