Organ transplantation

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Identification of the Donor-specific Regulatory T Cell Repertoire for Tracking in Human Transplant Recipients

Thursday, June 15
5:45 PM - 7:00 PM

We aimed to optimize the ability to identify and track donor alloantigen-specific Tregs in transplant recipients using a high throughput TCR sequencing-based approach. On three healthy control samples, we looked for TCRb CDR3 sequences identified in unstimulated FACS-sorted Tregs (CD4+CD25+CD127-) and CD4 “nonTregs” (CD4+CD25-)in several activated T cell populations: 1) CFSElow CD4 cells from bulk CFSE-MLR; 2) FACS-sorted Tregs (CD4+CD25+CD127-) expanded by culture with irradiated activated donor B cells; 3) FACS-sorted Tregs expanded by primary MLR in the presence of CTLA-4Ig (Belatacept), and following donor restimulation in secondary MLR with Belatacept.  Overlap between unstimulated Tregs and CFSElow-MLR CD4 cells included 20 to 318 unique sequences; Tregs expanded with donor B cells included 1836 to 5139 unique sequences; primary Belatacept MLRs included 42,189 to 92,312 unique sequences; and secondary Belatacept MLRs 18,513 to 25,357 unique sequences.  The primary MLRs with Belatacept had similar TCRb repertoires to the unstimulated Treg repertoire (top 100 sequences Jensen-Shannon Divergence [JSD] values: 0.05-0.13), suggesting minimal enrichment for donor-specificity.  JSD values comparing the other methods to each other and to the unstimulated Treg repertoires showed greater divergence.  The cumulative frequency of nonTregs was higher than that of Tregs in the secondary Belatacept MLR sequences, suggesting the prominent induction of Tregs from nonTregs, whereas the reverse was true in the Treg culture with donor B cells.  These data indicate that activated donor B cells preferentially expand natural donor-specific Tregs and that additional natural Treg sequences are identified by each of the methods evaluated.

Thomas M. Savage

Columbia Center for Translational Immunology, Columbia University

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    Aleksander Obradovic

    Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

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      Brittany Shonts

      Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

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        Karl Berglund

        Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

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          Susan Dewolf

          Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

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            Saiping Lau

            Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

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              Julien Zuber

              Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

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                Yufeng Shen

                Columbia University

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                  Laurence A. Turka

                  Professor
                  Massachusetts General Hospital/ Harvard Medical School

                  Dr. Turka received his MD degree from the Yale University School of Medicine, and trained in Internal Medicine at Yale-New Haven Hospital. Dr. Turka was a renal fellow at the Brigham and Women’s Hospital, where his research fellowship was conducted in Dr. Charles B. Carpenter’s laboratory. In 2009 Dr. Turka came to Boston and is currently located at the Massachusetts General Hospital, where he is Co-Director of the Center for Transplantation Sciences, and the Harold and Ellen Danser Professor of Surgery at Harvard Medical School. Dr. Turka has been continuously funded by the NIH for the past 25 years, and has also received funding from the American Heart Association, the National Kidney Foundation, and the Juvenile Diabetes Foundation International. He received the Young Investigator Award from the American Society of Nephrology in 1996, and from the American Society of Transplantation in 1998. He is a former President of the American Society of Transplantation and recipient of their Excellence in Mentoring Award. He has served as a permanent member of the SAT study section, and Chair of the NIAID Board of Scientific Counselors. He is a former section editor of The Journal of Immunology, past associate editor of The American Journal of Transplantation, and Editor in Chief of The Journal of Clinical Investigation. He currently serves as Deputy Director of the Immune Tolerance Network. He was elected to membership in the American Society for Clinical Investigation in 1995, and the Association of American Physicians in 2003.

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                    Megan Sykes

                    Columbia Center for Translational Immunology, Columbia University

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                      Identification of the Donor-specific Regulatory T Cell Repertoire for Tracking in Human Transplant Recipients



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