Renal transplantation has become the treatment of choice for patients with end-stage renal disease. However, acute renal allograft rejection (ARAR) remains a major complication after kidney transplantation and is associated with significant morbidity and mortality. Importantly, ARAR remains the strongest predictor of long-term renal allograft injury and survival. Currently known risk factors do not allow for an accurate risk assessment of ARAR. Genetic variability in key immunoregulatory molecules likely contributes to the differential risk of ARAR in the transplant population and assessment of genetic variants through differences in single nucleotide polymorphisms (SNPs) can provide valuable markers for ARAR risk assessment. In addition, we currently lack a non-invasive, cost-effective clinical test to diagnose ARAR. Therefore, in this proposal, we plan to 1) utilize our innovative genetic platform to identify immunogenetic biomarkers for ARAR risk assessment and 2) assess the role of peripheral cytokine profiling for the diagnosis of ARAR. The goals of this Mid-Career Investigator Award are to expand Dr. Reza Abdi's patient-oriented research program towards the development of better diagnostic and prognostic strategies for ARAR in renal transplant patients, further enhance Dr. Abdi's mentoring skills, and provide him with the resources and support to foster the development of trainees interested in patient-oriented research in transplantation. This research proposal is built upon the candidate's prior research identifying genetic biomarkers in transplantation and is strengthened by his multidisciplinary collaborations. These projects offer a unique opportunity for mentees to train in patient-oriented clinical and translational transplantation research that is at the intersection of immunology, genetics and transplantation. From this training vehicle, mentees will gain skills to carry out patient-oriented research in transplantation, learn to apply cutting-edge immunogenetic testing and gain hands-on experience in translational research examining the molecular and cellular mechanisms that lead to ARAR. The rich resources and infrastructure at Harvard Medical School and the Brigham and Women's Hospital Renal Division/Transplantation Research Center provide an outstanding scientific research environment to train the next generation of researchers in transplantation. These studies will not only help identify novel immunogenetic biomarkers for predicting ARAR and help in the creation of a clinical tool for diagnosing ARAR, but will also advance our understanding of the pathogenesis of ARAR and greatly assist in the development of innovative therapies in renal transplantation.
Acute renal allograft rejection (ARAR) is a major complication after renal transplantation and remains the strongest predictor of long-term renal allograft injury and survival. The goals of this project are to identify novel immunogenetic predictors of ARAR and develop an innovative diagnostic and prognostic tool for ARAR. These studies carry high significance in reducing the burden of ARAR and improving outcomes in renal transplant patients.
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|Sula Karreci, Esilida; Eskandari, Siawosh K; Dotiwala, Farokh et al. (2017) Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation. JCI Insight 2:|