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

点击翻译按钮获取中文摘要

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to sibling minor antigen, as also determined by the DTH assay, will predict the ability of the subjects to safely be withdrawn from CNI.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.