Research ArticleTransplantation

Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients

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Science Translational Medicine  28 Jan 2015:
Vol. 7, Issue 272, pp. 272ra10
DOI: 10.1126/scitranslmed.3010760

Tolerating transplant

Transplant rejection remains a formidable barrier to successful organ transplantation. Recent advances, such as combined kidney and bone marrow transplantation (CKBMT), hint that rejection can be overcome by the induction of immune tolerance. Now, Morris et al. have developed a way to track T cells to determine how this tolerance works. They used high-throughput T cell receptor sequencing to find donor-reactive T cells before transplant and then tracked these clones after CKBMT. These donor-reactive T cells were reduced in CKBMT patients who achieved tolerance but not in a CKBMT patient who failed to achieve tolerance or in recipients of conventional, nontolerizing transplant protocols. These data suggest that clonal deletion is a mechanism of graft tolerance after CKBMT in humans.


T cell responses to allogeneic major histocompatibility complex antigens present a formidable barrier to organ transplantation, necessitating long-term immunosuppression to minimize rejection. Chronic rejection and drug-induced morbidities are major limitations that could be overcome by allograft tolerance induction. Tolerance was first intentionally induced in humans via combined kidney and bone marrow transplantation (CKBMT), but the mechanisms of tolerance in these patients are incompletely understood. We now establish an assay to identify donor-reactive T cells and test the role of deletion in tolerance after CKBMT. Using high-throughput sequencing of the T cell receptor B chain CDR3 region, we define a fingerprint of the donor-reactive T cell repertoire before transplantation and track those clones after transplant. We observed posttransplant reductions in donor-reactive T cell clones in three tolerant CKBMT patients; such reductions were not observed in a fourth, nontolerant, CKBMT patient or in two conventional kidney transplant recipients on standard immunosuppressive regimens. T cell repertoire turnover due to lymphocyte-depleting conditioning only partially accounted for the observed reductions in tolerant patients; in fact, conventional transplant recipients showed expansion of circulating donor-reactive clones, despite extensive repertoire turnover. Moreover, loss of donor-reactive T cell clones more closely associated with tolerance induction than in vitro functional assays. Our analysis supports clonal deletion as a mechanism of allograft tolerance in CKBMT patients. The results validate the contribution of donor-reactive T cell clones identified before transplant by our method, supporting further exploration as a potential biomarker of transplant outcomes.

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