Campath-1H & Calcineurin-Inhibitors in Renal Transplant

坎帕斯-1H

• 批准号: 7248796
• 负责人: Stuart Johnston Knechtle
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7248796
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Acute; Adopted; Adverse effects; Antibodies; Biological Assay; Biopsy; Biopsy Specimen; Blood; CD4 Positive T Lymphocytes; Cadaver; Calcineurin inhibitor; Cells; Chemistry; Chronic; Clinical; Clinical Trials; Cyclosporine; Data; Development; Dose; Evaluation; Funding; Genetic Markers; Histologic; Histology; Human; Ilex; Immune; Immunologic Monitoring; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Injury; Isoantibodies; Kidney; Kidney Transplantation; Learning; Life; Living Donors; Lymphocyte Activation; Lymphocyte Depletion; MabCampath; Maintenance; Maintenance Therapy; Malignant Neoplasms; Measurement; Measures; Mediating; Methodology; Methylprednisolone; Monitor; Monoclonal Antibody Campath-1H; Nature; Neoadjuvant Therapy; Opportunistic Infections; Organ Transplantation; Outcome; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pilot Projects; Population; Prednisone; Prograf; Protocols documentation; Randomized; Range; Rate; Regulation; Research Ethics Committees; Risk; Role; Sirolimus; Solid; Source; Steroids; T cell regulation; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Toxic effect; Transforming Growth Factor beta; Transplant Recipients; Transplantation; Universities; Wisconsin; Withdrawal; alemtuzumab; base; complement C4d; cost; day; design; experience; graft function; humanized monoclonal antibodies; immunocytochemistry; kidney allograft; mycophenolate mofetil; oncology; programs; reconstitution; response; tool

DESCRIPTION (provided by applicant): The University of Wisconsin renal transplant program in December 2002 adopted an immunosuppressive strategy consisting of Campath-1H induction (30 mg i.v. times 2), and maintenance immunosuppression consisting of a calcineurin inhibitor, mycophenolate mofetil, and low-dose steroids (methylprednisolone 10 mg a day). We have witnessed approximately 5% incidence of rejection with very few side effects. In order to test the hypothesis that these patients would do well with subsequent withdrawal of calcineurin inhibitors, a clinical trial has been IRB approved at this center for randomization 1:1 to either continue or discontinue calcineurin inhibitors beginning at least 2 months post-transplant. Tapering would occur over 3 months. Based on preliminary results derived in our renal transplant population using Campath-1H induction, we are evaluating four mechanistic assays to determine their usefulness in assessing the immune status of renal transplant patients, that is, whether they are safe to reduce immunosuppression or at risk for rejection. This application seeks to fund these four mechanistic assays to determine their usefulness in association with this clinical trial of calcineurin inhibitor withdrawal. Whether or not the clinical trial is successful in freeing patients from calcineurin inhibitor use, data and methodology derived from these mechanistic assays would be applicable to a broad range of organ transplant recipients and would guide development of immunologic monitoring tools in the field of transplantation. The four specific aims of this application are: 1. To assess donor-specific unresponsiveness in patients using a CFSE-based proliferation assay and T-lymphocyte activation response profile. 2. To assess the alloantibody response following transplantation in study patients to determine whether it is predictive of graft outcome (acute and chronic rejection) and/or correlates with histologic injury in 1- and 2-year biopsies. 3. To assess development of T cell regulation in patients using the trans-vivo DTH assay and evaluation of TGF-beta expression in protocol biopsies at one and two years. 4. To assess putative genetic markers of tolerance by correlating their expression in blood and biopsy specimens at 1 and 2 years post-transplant with graft function, immunosuppressive drugs, and the measurements obtained in specific aims 1-3 above.

描述（由申请人提供）：威斯康星州大学肾移植项目于2002年12月采用了一种免疫抑制策略，包括Campath-1H诱导（30 mg静脉注射2次）和维持免疫抑制，包括钙调磷酸酶抑制剂、吗替麦考酚酯和低剂量类固醇（甲泼尼龙10 mg/天）。我们目睹了大约5%的排斥反应发生率，而且副作用很少。为了检验这些患者在随后停用钙调磷酸酶抑制剂后表现良好的假设，IRB已批准在该中心进行一项临床试验，以1：1的比例随机分配，从移植后至少2个月开始继续或停用钙调磷酸酶抑制剂。逐渐变细将在3个月内发生。 基于在我们的肾移植人群中使用Campath-1H诱导的初步结果，我们正在评估四种机制检测，以确定其在评估肾移植患者免疫状态中的有用性，即，他们是否可以安全地减少免疫抑制或有排斥反应的风险。本申请旨在资助这四种机制测定，以确定其与钙调磷酸酶抑制剂戒断临床试验相关的有用性。无论临床试验是否成功地使患者摆脱钙调磷酸酶抑制剂的使用，从这些机制分析中获得的数据和方法将适用于广泛的器官移植受者，并将指导移植领域免疫监测工具的开发。这项申请的四个具体目标是： 1.使用基于CFSE的增殖试验和T淋巴细胞活化反应谱评估患者的供体特异性无反应性。 2.评估研究患者移植后的同种抗体反应，以确定其是否可预测移植物结局（急性和慢性排斥反应）和/或与1年和2年活检的组织学损伤相关。 3.使用体内DTH试验评估患者T细胞调节的发展，并在1年和2年时评价方案活检中的TGF-β表达。 4.通过将移植后1年和2年的血液和活检标本中的表达与移植物功能、免疫抑制药物和上述特定目标1-3中获得的测量值相关联，评估耐受性的推定遗传标记。