Minor H Antigen Regulatory Networks as an Alternative to Calcineurin Inhibitors i

次要 H 抗原调节网络作为钙调神经磷酸酶抑制剂的替代品 i

• 批准号: 7305369
• 负责人: William J Burlingham
• 金额: $ 18.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-13 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7305369
• 关键词: Abbreviations; Acute; Acute Disease; Allografting; Animals; Antigens; Back; Biological Assay; Calcineurin inhibitor; Cell Count; Cells; Chronic; Clinical; Clinical Trials; Cyclosporine; Delayed Hypersensitivity; Development; Donor person; Effector Cell; End stage renal failure; Enrollment; Eragrostis; Explosion; Failure; Freezing; Functional disorder; Goals; HLA Antigens; Healthcare; Heart; Immune; Immune Tolerance; Immune response; Immunosuppression; Immunosuppressive Agents; Individual; Kidney; Kidney Failure; Kidney Transplantation; Kinetics; Life; Living Donors; Localized; Lung; Measures; Mediating; Minor; Minor Histocompatibility Antigens; Monitor; Mycophenolate; Mycophenolic Acid; Nephrotoxic; Normal Cell; Organ Transplantation; Outcome; Patient Discharge; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Price; Quality of life; Randomized; Randomized Clinical Trials; Recovery; Regulation; Renal function; Resolution; Risk; Sampling; Siblings; Sodium; Solid; Solutions; Structure; Survivors; Testing; Therapeutic immunosuppression; Time; Today; Translational Research; Transplant Recipients; Transplantation; Treatment Protocols; Uncertainty; Universities; Wisconsin; Withdrawal; bacterial H antigen; base; chemokine; cohort; cytokine; drug withdrawal; experience; fluorouracil/methotrexate/mitoxantrone protocol; graft function; improved; in vitro Assay; inhibitor/antagonist; mycophenolate mofetil; nephrotoxicity; prevent; response

DESCRIPTION (provided by applicant): The introduction of calcineurin inhibitors (CNI) in 1983 resulted in better early allograft survival in solid organ transplant recipients; however, more than 20 years after their introduction, the negative impacts of CNI are apparent. CNI induced nephrotoxicity is a leading cause of renal transplant failure, especially in recipients of well-matched HLA identical renal transplants (HLA-ID) and heart and lung transplant recipients, often resulting in a need for kidney transplants in the latter. While the simple reduction of CNI inhibitors would appear to be the best resolution to this "disease", acute and chronic allograft rejection are often the consequence of immunosuppression withdrawal. There are currently no commercial assays to predict the patients who can safely reduce their level of immunosuppressive medication. We have utilized a trans-vivo delayed type hypersensitivity assay (DTH) to determine the level of immune regulation in patients both on and off immunosuppression. In this pilot study, we propose to utilize the DTH assay to monitor the pattern of change over time of immune regulation to minor H antigens in recipients of living donor transplants. We will sample PBMC after transplant from patients 1) on whom we have performed pre-transplant analysis and who are still taking immunosuppressive medication and 2) in HLA-ID matched patients, before and after CNI withdrawal to Mycophenolic Acid monotherapy in a randomized clinical trial. We hypothesize that the level of immune regulation vs. sensitization to sibling minor antigen, as also determined by the DTH assay, will predict the ability of the subjects to safely be withdrawn from CNI. While we believe the DTH assay is the best predictor of immune regulation and will therefore be predictive of successful CNI withdrawal, it is an assay which is not readily transferable to the larger clinical setting or larger clinical trials. Therefore a major focus of this pilot study will be to develop alternative chemokine, enzymatic and cytokine based assays which parallel the DTH assay, but which are practical on a larger scale. If the initial pilot study shows: 1) good predictive power of DTH regulation for successful CNI withdrawal and 2) development of alternate assays which mimic the DTH results, it will embolden transplant clinicians to expand CNI withdrawal to a larger cohort of patients and patients with 0 HLA-mismatched deceased donor transplants or less well matched recipients of living donor transpalnts (e.g. 4-5 HLA antigen-matched haploidentical donors). Calcineurin inhibitors (CNI) are by far the most common agents used to prevent allograft rejection today, yet they have become a leading cause of kidney failure. Removing CNI to rescue kidney function has proved problematic due to uncertainty regarding the patient's immune status. This pilot clinical trial is aimed at removing CNI from a subset of kidney transplants that are mismatched for minor H antigens only (HLA- identical sibling donors), while at the same time assessing the validity of trans-vivo DTH and surrogate in vitro assays to accurately predict successful CNI withdrawal. Improving our understanding of the dynamics of donor minor H antigen-specific immune regulation will open the way to minimization of immune suppression in more high-risk transplant recipients who may currently be suffering from CNI-induced renal dysfunction.

描述（由申请人提供）：1983年引入钙调神经磷酸酶抑制剂（CNI）导致实体器官移植受者的早期同种异体移植物存活率更好;然而，在其引入20多年后，CNI的负面影响是显而易见的。CNI诱导的肾毒性是肾移植失败的主要原因，特别是在良好匹配的HLA相同肾移植（HLA-ID）的接受者以及心脏和肺移植接受者中，通常导致后者需要肾移植。虽然简单减少CNI抑制剂似乎是这种“疾病”的最佳解决方案，但急性和慢性同种异体移植排斥反应通常是免疫抑制剂撤药的结果。目前还没有商业化的检测方法来预测可以安全地降低免疫抑制药物水平的患者。我们已经利用了一个trans-vivo迟发型超敏反应试验（DTH），以确定患者的免疫调节水平和关闭免疫抑制。在这项试点研究中，我们建议利用DTH检测来监测活体供者移植受体对小H抗原的免疫调节随时间变化的模式。我们将在随机临床试验中，在CNI停药至麦考酚酸单药治疗之前和之后，从1）我们已进行移植前分析且仍在服用免疫抑制药物的患者和2）HLA-ID匹配的患者中采集移植后PBMC样本。我们假设免疫调节水平与对同胞次要抗原的致敏水平（也通过DTH试验确定）将预测受试者安全退出CNI的能力。虽然我们相信DTH检测是免疫调节的最佳预测因子，因此可以预测CNI成功戒断，但这种检测方法不容易转移到更大的临床环境或更大的临床试验中。因此，该试点研究的主要重点将是开发替代的基于趋化因子、酶和细胞因子的测定，其与DTH测定平行，但在更大规模上是实用的。如果初步试点研究显示：1）DTH调节对于成功的CNI戒断的良好预测能力和2）模拟DTH结果的替代测定的开发，这将鼓励移植临床医生将CNI撤出扩大到更大的患者队列，以及HLA不匹配的死亡供体移植或匹配较差的活体供体移植受者的患者。（例如，4-5个HLA抗原匹配的单倍体相合供体）。钙调神经磷酸酶抑制剂（CNI）是目前最常用的预防同种异体移植排斥反应的药物，但它们已成为肾衰竭的主要原因。由于患者免疫状态的不确定性，去除CNI以挽救肾功能已被证明是有问题的。这项试点临床试验的目的是从仅与次要H抗原不匹配的肾移植子集中去除CNI（HLA相同的兄弟姐妹供体），同时评估跨体DTH和替代体外测定的有效性，以准确预测成功的CNI撤回。提高我们对供体次要H抗原特异性免疫调节动态的理解，将为目前可能患有CNI诱导的肾功能不全的高危移植受者的免疫抑制最小化开辟道路。