@article{aa5c49b627ef4f59a907c927cfcc3715,
title = "Distinct peripheral blood molecular signature emerges with successful tacrolimus withdrawal in kidney transplant recipients",
abstract = "Tacrolimus (Tac) is an effective anti-rejection agent in kidney transplantation, but its off-target effects make withdrawal desirable. Although studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs unsuccessful Tac removal are unknown. We performed microarray analyses of peripheral blood mononuclear cells (PBMC) RNA from subjects enrolled in the Clinical Trials in Organ Transplantation-09 study in which we randomized stable kidney transplant recipients to Tac withdrawal or maintenance of standard immunosuppression beginning 6 months after transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a downregulatory and proapoptotic gene program enriched within T cells. Functional analyses suggested stronger donor-reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data from a small, but unique, patient cohort support the conclusion that successful Tac withdrawal is not simply due to absence of donor-reactive immunity but rather is associated with an active immunological process.",
keywords = "genomics, immunobiology, immunosuppressant - calcineurin inhibitor: tacrolimus, immunosuppression/immune modulation, kidney (allograft) function/dysfunction, translational research/science",
author = "Paolo Cravedi and Miguel Fribourg and Weijia Zhang and Zhengzi Yi and Elena Zaslavsky and German Nudelman and Lisa Anderson and Susan Hartzell and Sophie Brouard and Heeger, {Peter S.}",
note = "Funding Information: This work was supported in part by National Institutes of Health (NIAID) U01 AI63594 awarded to PSH. The authors sincerely thank the CTOT-09 site investigators and staff for their efforts including Donald E. Hricik (University Hospitals Case Medical Center, Cleveland, OH, USA), Richard N. Formica (Yale University School of Medicine, New Haven, CT, USA), Peter Nickerson, David Rush, Chris Wiebe, and Ian Gibson (University of Manitoba, Winnipeg, Manitoba, Canada), Robert L. Fairchild and Emilio D. Poggio (Cleveland Clinic, Cleveland, OH, USA), Kathryn Tinckam (University of Toronto, Toronto, Canada) Suphamai Bunnapradist (University of California at Los Angeles Medical Center, Los Angeles, CA, USA), Milagros Samaniego-Picota (University of Michigan Medical Center, Ann Arbor, MI, USA), Daniel C. Brennan (Washington University, St. Louis, MO, USA), Bernd Schr{\"o}ppel (Icahn School of Medicine at Mount Sinai, NY, NY, USA) Osama Gaber (Houston Methodist Hospital, Houston, TX and Weil Cornell Medical College, NY, NY, USA), Brian Armstrong and David Ikle (Rho, Chapel Hill, NC, USA) Helena Diop and Nancy D. Bridges (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD). The authors thanks Mandy Ford (Emory, Atlanta) for her critical insights. The authors also thank the late Dan Salomon, Scripps La Jolla, for performing the microarray studies. Funding Information: This work was supported in part by National Institutes of Health (NIAID) U01 AI63594 awarded to PSH. The authors sincerely thank the CTOT‐09 site investigators and staff for their efforts including Donald E. Hricik (University Hospitals Case Medical Center, Cleveland, OH, USA), Richard N. Formica (Yale University School of Medicine, New Haven, CT, USA), Peter Nickerson, David Rush, Chris Wiebe, and Ian Gibson (University of Manitoba, Winnipeg, Manitoba, Canada), Robert L. Fairchild and Emilio D. Poggio (Cleveland Clinic, Cleveland, OH, USA), Kathryn Tinckam (University of Toronto, Toronto, Canada) Suphamai Bunnapradist (University of California at Los Angeles Medical Center, Los Angeles, CA, USA), Milagros Samaniego‐Picota (University of Michigan Medical Center, Ann Arbor, MI, USA), Daniel C. Brennan (Washington University, St. Louis, MO, USA), Bernd Schr{\"o}ppel (Icahn School of Medicine at Mount Sinai, NY, NY, USA) Osama Gaber (Houston Methodist Hospital, Houston, TX and Weil Cornell Medical College, NY, NY, USA), Brian Armstrong and David Ikle (Rho, Chapel Hill, NC, USA) Helena Diop and Nancy D. Bridges (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD). The authors thanks Mandy Ford (Emory, Atlanta) for her critical insights. The authors also thank the late Dan Salomon, Scripps La Jolla, for performing the microarray studies. Publisher Copyright: {\textcopyright} 2020 The American Society of Transplantation and the American Society of Transplant Surgeons",
year = "2020",
month = dec,
doi = "10.1111/ajt.15979",
language = "English",
volume = "20",
pages = "3477--3485",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "12",
}