Campath-1H & Calcineurin-Inhibitors in Renal Transplant

坎帕斯-1H

• 批准号: 6936639
• 负责人: Stuart Johnston Knechtle
• 金额: $ 36.38万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936639
• 关键词: artificial immunosuppression; biopsy; clinical research; clinical trials; cyclosporines; delayed hypersensitivity; dosage; genetic markers; human subject; human therapy evaluation; human tissue; immune tolerance /unresponsiveness; immunocytochemistry; isoantibody; kidney transplantation; leukocyte activation /transformation; mixed lymphocyte reaction test; monoclonal antibody; mycophenolate mofetil; neutralizing antibody; patient oriented research; prednisone; transplant rejection

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.

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).我们目睹了大约5％的拒绝发生率，副作用很少。为了检验以下假设，即这些患者随后戒断钙调蛋白抑制剂可以很好地表现出色，在本植物后至少2个月开始，在该随机化中心批准了IRB的临床试验，以继续进行1：1的IRB。逐渐减少3个月。 基于使用CAMPATH-1H诱导在我们的肾移植人群中得出的初步结果，我们正在评估四种机械测定法，以确定它们在评估肾脏移植患者的免疫状态时的实用性，即是否可以安全地减少免疫抑制或有抑制风险。该应用程序旨在为这四种机械测定法提供资金，以确定其与钙调神经蛋白抑制剂戒断的临床试验相关的有用性。临床试验是否成功地使患者免于使用钙调神经素抑制剂的使用，从这些机械测定中得出的数据和方法都适用于广泛的器官移植受者，并将指导移植领域中免疫学监测工具的开发。该应用程序的四个具体目标是： 1。使用基于CFSE的增殖测定法和T淋巴细胞激活反应曲线评估患者的供体特异性无反应性。 2。在研究患者移植后评估同种抗体反应，以确定其是否可以预测1年和2年的活检中的移植结果（急性和慢性排斥）和/或与组织学损伤相关。 3。用于评估患者中T细胞调节的开发，并在一年和两年内评估协议活检中TGF-β表达的评估。 4。通过将移植物后1和2年的血液和活检标本中的表达与移植功能，免疫抑制药物以及上面的特定目标1-3获得的测量值相关联，以评估耐受性的推定遗传标记。