title: Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients.
abstract: 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.
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Heather
authors: H
authors: Morris
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Susan
authors: S
authors: DeWolf
authors: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Harlan
authors: H
authors: Robins
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Ben
authors: B
authors: Sprangers
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Samuel A
authors: SA
authors: LoCascio
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Brittany A
authors: BA
authors: Shonts
authors: Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Tatsuo
authors: T
authors: Kawai
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Waichi
authors: W
authors: Wong
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Suxiao
authors: S
authors: Yang
authors: Columbia University Medical Center, New York, NY 10032, USA.
authors: Julien
authors: J
authors: Zuber
authors: Columbia University Medical Center, New York, NY 10032, USA. megan.sykes@columbia.edu ys2411@columbia.edu.
authors: Yufeng
authors: Y
authors: Shen
authors: Columbia University Medical Center, New York, NY 10032, USA. megan.sykes@columbia.edu ys2411@columbia.edu.
authors: Megan
authors: M
authors: Sykes
mesh_terms: D064591:Allografts; D016026:Bone Marrow Transplantation; D017637:Clonal Deletion; D022801:Complementarity Determining Regions / Q000378:metabolism; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000276:immunology* / Q000601:surgery; D016030:Kidney Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D023001:Transplantation Tolerance; D016896:Treatment Outcome
chemical_list: D022801:Complementarity Determining Regions; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell
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