Nicholas Borcherding, M.D., Ph.D.

ABSTRACT

Kidney transplantation extends life expectancy by 10–15 years compared with dialysis, yet more than half of transplants fail within ten years, and current monitoring detects rejection only after injury has occurred. This project applies TIRTL-seq — a newly published platform that generates over 100,000 paired αβ T cell receptor (TCR) sequences per sample at one-tenth the cost of single-cell methods — to 120 longitudinal blood samples from 40 highly sensitized kidney transplant recipients sampled before transplant and at 1 and 4 weeks after. The team will track expanding, structurally convergent T cell clones and test whether paired TCR network topology, integrated with donor-recipient HLA mismatch data, predicts biopsy-proven rejection; their preliminary β-chain-only network model already predicts rejection with an AUC of 0.808, and generalizability will be tested in two published external cohorts (n=244). Success would support pre-transplant risk stratification, non-invasive rejection detection weeks before creatinine rises, and safe immunosuppression minimization — each a direct pathway to longer graft and patient survival — and will generate preliminary data for an NIH R01.
Lay Summary:
Kidney transplantation is the best treatment for end-stage kidney disease, but by the time rejection is detected with today’s blood tests or biopsies, irreversible damage has often already occurred. Recipients also take lifelong immunosuppressive drugs that raise the risk of infections, cancers, and heart disease — the leading causes of late death after transplantation.
This project develops a blood test that detects the specific T cells attacking a transplanted kidney before damage occurs. T cells recognize targets using a receptor called the TCR, and the ones attacking a transplant multiply after surgery. Using a new technology that reads these receptors at a fraction of previous costs, the team will study 40 high-risk patients before and shortly after transplant, looking for rapidly expanding T cells and groups of cells that share recognition patterns. If successful, the test could tell doctors before transplantation who needs stronger anti-rejection medication, detect rejection from a simple blood draw weeks earlier than current methods, and identify patients who can safely reduce their immunosuppressive drugs — improving both the lifespan of the transplant and the long-term health of the more than 250,000 Americans living with a kidney transplant.