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; 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.

项目摘要/摘要 拟议的临床研究的目的是诱导对肾脏和造血细胞组合的耐受性 用总淋巴样辐射（TLI）和抗胸腺细胞球蛋白（ATG）进行调节后的移植。 鉴于相关的生活HLA单倍型与捐助者或无关的活捐赠者的移植 匹配3 HLA抗原。预计宽容的建立将消除通常的终身需求 免疫抑制（IS）药物和随之而来的副作用，使得戒毒将是 在没有后续拒绝证据的情况下完成。拟议的研究以我们在 在大约80％的完全HLA中成功诱导嵌合和宽容的授予期 匹配的患者，在相关HLA单倍型中建立持续高水平混合嵌合的能力 匹配的患者，25 HLA匹配的100％肾脏移植物存活和20 HLA不匹配的患者 在过去的15年中，参加了公差方案。我们将测试高水平的假设 持续一年以上的混合嵌合物将在戒毒期间和之后保持一年以上，并且 导致公差。我们假设将通过同种反应性T细胞克隆的证据来预测公差 通过TCR基因的高通量测序测量的缺失，缺乏供体特异性的发展 抗体（DSA），尿液中缺乏炎性细胞PCR产物。淋巴机的变化 通过确定平衡的变化，将监测促进耐受性的组织 效应T细胞和免疫抑制调节细胞，包括单核细胞和髓样衍生的抑制剂 血液中的细胞（MDSC）。为了评估患者的长期结局，我们建议建立一个 自成立以来，所有参加我们公差方案的患者的疗效和风险注册表和风险 我们中心和国家注册中心的护理患者标准。此外，我们将长期执行 免疫监测参数以衡量嵌合的持续性，供体特定的反应性 MLR和T细胞克隆曲目。总之，我们将尝试诱导宽容，确定机制 可以适当地指导药物的预测因子，并确定免疫的耐用性 宽容的改变。