Gene and Cytokine Expression in Tolerance and GVHD

耐受性和 GVHD 中的基因和细胞因子表达

• 批准号: 8134262
• 负责人: Robert Lowsky
• 金额: $ 39.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134262
• 关键词: Antithymoglobulin; B-Lymphocytes; Biological Assay; Bone Marrow; CD4 Positive T Lymphocytes; Cancer Patient; Cell Transplantation; Cell Transplants; Cells; Chimerism; Clinical Research; Clinical Treatment; Clinical Trials; Cross-Sectional Studies; Cyclosporine; Cytokine Gene; Dendritic Cells; Development; Drug usage; Enrollment; Freedom; Future; Gene Chips; Gene Expression; Genes; Goals; Graft Rejection; Hematopoietic; Hormones; IL2RA gene; Immune; Immune Tolerance; Immunologic Monitoring; Immunosuppressive Agents; Interferons; Interleukin-10; Interleukin-4; Kidney; Kidney Transplantation; Lymphatic Irradiation; Lymphoma; Maintenance; Molecular; Monitor; Natural Killer Cells; Outcome; Parents; Patient Monitoring; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Prevention; Procedures; Process; Production; Regimen; Regulatory T-Lymphocyte; Research Design; Sorting - Cell Movement; T-Lymphocyte; T-Lymphocyte Subsets; Time; Transplant Recipients; Transplantation; Withdrawal; base; chronic graft versus host disease; conditioning; cytokine; design; drug withdrawal; graft function; graft vs host disease; improved; insight; leukemia/lymphoma; monocyte; mycophenolate mofetil; novel; patient safety; preclinical study; prevent; tumor

DESCRIPTION (provided by applicant): Studies are proposed to enhance and improve the immune monitoring of the peripheral blood mononuclear cells (PBMCs) of patients enrolled in two parent clinical trials; one designed to induce immune tolerance to combined kidney and hematopoietic cell transplants and another designed to prevent graft versus host disease (GVHD) after hematopoietic cell transplantation (HCT) for the treatment of leukemia and lymphoma. The goals of the proposed immune monitoring are to use serial analyses of gene microarrays and patterns of intracellular cytokine production to predict which patients can be safely withdrawn from all immunosuppressive drugs at 6 months after transplantation without the subsequent development of rejection episodes in the case of the kidney transplant patients and without the development of GVHD in the case of the hematolymphoid cancer patients. The gene microarray studies build upon recent cross sectional studies that show a "tolerance" gene expression pattern in kidney transplant patients with good graft function off drugs, and a "GVHD" expression pattern that differentiates patients with and without chronic GVHD. We plan to apply the microarray assays to serial longitudinal monitoring of patients in the two trials. In addition, our preclinical and clinical studies of the monitoring of cytokine production patterns of T cell subsets has delineated an IL-4 and IL-10 increase pattern that is associated with the successful induction of tolerance and prevention of GVHD. We will apply the serial monitoring of the changed cytokine patterns to help guide the safe withdrawal of all immunosuppressive drugs in concert with the gene array studies in the future. In addition to providing information about guidance of drug withdrawal, the studies are designed to provide further insight into the cellular and molecular immune mechanisms of tolerance and GVHD protection.

描述（由申请人提供）：本研究旨在加强和改善两项母临床试验患者外周血单个核细胞（PBMCs）的免疫监测；一种旨在诱导对肾和造血细胞联合移植的免疫耐受，另一种旨在预防用于治疗白血病和淋巴瘤的造血细胞移植（HCT）后的移植物抗宿主病（GVHD）。所提出的免疫监测的目标是使用基因微阵列和细胞内细胞因子产生模式的系列分析来预测哪些患者可以在移植后6个月安全地停用所有免疫抑制药物，而不会发生肾移植患者的排斥反应，而不会发生血淋巴癌患者的GVHD。基因微阵列研究建立在最近的横断面研究的基础上，该研究表明，在没有药物的移植功能良好的肾移植患者中存在“耐受”基因表达模式，以及区分慢性GVHD患者和非慢性GVHD患者的“GVHD”表达模式。我们计划在这两项试验中将微阵列检测应用于患者的连续纵向监测。此外，我们对T细胞亚群细胞因子产生模式监测的临床前和临床研究已经描述了IL-4和IL-10增加模式，这与成功诱导耐受性和预防GVHD有关。我们将应用细胞因子模式变化的连续监测，以帮助指导所有免疫抑制药物的安全停药，并配合未来的基因阵列研究。除了提供有关停药指导的信息外，这些研究还旨在进一步了解耐受和GVHD保护的细胞和分子免疫机制。