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

描述(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早期移植物存活率提高；然而，在它们被引入20多年后，CNI的负面影响是显而易见的。CNI引起的肾毒性是肾移植失败的主要原因，尤其是在完全相合的人类白细胞抗原相合肾移植(HLAID)受者和心肺移植受者中，后者往往需要肾移植。虽然简单地减少CNI抑制剂似乎是解决这一“疾病”的最好方法，但急性和慢性同种异体移植排斥反应往往是免疫抑制停药的结果。目前还没有商业分析来预测哪些患者可以安全地减少免疫抑制药物的水平。我们利用体内延迟型超敏反应试验(DTH)来确定接受和不接受免疫抑制的患者的免疫调节水平。在这项初步研究中，我们建议利用DTH试验来监测活体供体移植受者对微小H抗原的免疫调节随时间的变化模式。我们将从患者移植后的PBMC中取样：1)我们对其进行了移植前分析，并且仍在服用免疫抑制药物；2)在随机临床试验中，在人类白细胞抗原-ID相合的患者中，CNI停用霉酚酸单一疗法前后。我们假设，通过DTH试验确定的对同胞次要抗原的免疫调节水平与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，因此将预测CNI成功停用，但它不容易转移到更大的临床环境或更大的临床试验。因此，这项初步研究的主要重点将是开发替代的趋化因子、酶和细胞因子检测方法，它们与DTH检测平行，但在更大范围内是实用的。如果初步研究表明：1)DTH调节对成功撤除CNI的良好预测能力；2)开发模拟DTH结果的替代检测方法，将鼓励移植临床医生将CNI撤除扩大到更大的患者队列，以及0个不相合的已故供者移植或不太匹配的活体供者移植受者(例如4-5个HLA抗原匹配的半相合供者)。到目前为止，钙调神经磷酸酶抑制剂(CNI)是目前用于预防同种异体移植排斥反应的最常见的药物，但它们已成为导致肾衰竭的主要原因。由于患者免疫状态的不确定性，移除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有少量H抗原不匹配的肾移植子集(人类白细胞抗原相合的同胞捐赠者)中去除CNI，同时评估体内DTH和体外替代试验的有效性，以准确预测成功的CNI撤除。提高我们对供体微小H抗原特异性免疫调节动态的了解，将为更多高危移植受者减少免疫抑制开辟道路，这些受者目前可能患有CNI所致的肾功能障碍。

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.