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

描述（由申请人提供）：1983年引入钙调磷酸酶抑制剂（CNI）可提高实体器官移植受者的早期同种异体移植存活率；然而，在它们被引入20多年后，CNI的负面影响显而易见。CNI引起的肾毒性是肾移植失败的主要原因，特别是在HLA- id匹配良好的肾移植受者和心肺移植受者中，往往导致后者需要肾移植。虽然简单地减少CNI抑制剂似乎是解决这种“疾病”的最佳方法，但急性和慢性同种异体移植排斥反应往往是免疫抑制退出的后果。目前还没有商业试验来预测哪些患者可以安全地减少免疫抑制药物的剂量。我们利用跨体延迟型超敏试验（DTH）来确定免疫抑制和关闭患者的免疫调节水平。在这项初步研究中，我们建议利用DTH检测来监测活体供体移植受者对少量H抗原的免疫调节随时间的变化模式。在一项随机临床试验中，我们将对移植后的患者进行PBMC采样：1)我们进行了移植前分析并仍在服用免疫抑制药物的患者；2)HLA-ID匹配的患者，在CNI停药前后接受霉酚酸单药治疗。我们假设，同样由DTH测定确定的免疫调节水平与对同胞小抗原的致敏水平，将预测受试者安全退出CNI的能力。虽然我们认为DTH检测是免疫调节的最佳预测指标，因此可以预测CNI的成功退出，但它是一种不容易转移到更大的临床环境或更大的临床试验的检测。因此，这项试点研究的主要重点将是开发替代的趋化因子、酶和基于细胞因子的检测方法，这些方法与DTH检测方法平行，但在更大规模上是实用的。如果最初的试点研究显示：1)DTH调节对成功的CNI退出有良好的预测能力；2)模拟DTH结果的替代检测的发展，它将鼓励移植临床医生将CNI退出扩大到更大的患者队列，以及HLA不匹配的死亡供体移植患者或不太匹配的活体供体移植受体（例如4-5个HLA抗原匹配的单倍相同供体）。钙调磷酸酶抑制剂（CNI）是目前用于预防同种异体移植排斥反应的最常用药物，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，切除CNI以挽救肾功能已被证明是有问题的。该临床试验旨在从仅与次要H抗原（HLA-相同的兄弟供体）不匹配的肾移植亚群中去除CNI，同时评估跨体DTH和体外替代检测的有效性，以准确预测CNI的成功退出。提高我们对供体小H抗原特异性免疫调节动力学的理解，将为目前可能患有cni诱导肾功能障碍的更多高危移植受者的免疫抑制最小化开辟道路。

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.