T Cell Alloreactivity and Organ Transplant Risk Stratification Models Using High-Resolution HLA and Genomic Data

The conventional focus for histocompatibility in clinical solid organ transplantation focuses on humeral immunity, avoiding donor HLA molecules against which the recipient has pre-existing alloantibodies capable of mediating hyperacute rejection. While this is a practical approach mitigating some immunologic risk based on clinically available information, it does not address the inherent risks of T cell alloreactivity, which is a significant contributor to allograft rejection and requires life-long immunosuppression. In this proposal, we will leverage sequencing technologies and approaches adapted from immune-oncology to identify HLA allele-specific factors in solid organ transplant donors and recipients driving T cell alloimmune responses. We will develop a computational algorithm, CHART, to predict donor/recipient pair-specific T cell alloreactivity and risk of solid organ transplant rejection, with the goal toward precision medicine approaches for histocompatibility and personalized immunosuppression.