Sandy Feng1, John C Bucuvalas2, George V Mazariegos3, John C Magee4, Alberto Sanchez-Fueyo5, Katharine M Spain6, Andrew Lesniak7, Sai Kanaparthi8, Emily Perito9, Veena L Venkat10, Bryna E Burrell8, Estella M Alonso11, Nancy D Bridges12, Edward Doo13, Nitika A Gupta14, Ryan W Himes15, David Ikle6, Annette M Jackson16, Steven J Lobritto17, Juan Jose Lozano18, Mercedes Martinez17, Vicky L Ng19, Elizabeth B Rand20, Averell H Sherker13, Shikha S Sundaram21, Yumirle P Turmelle22, Michele Wood-Trageser7, Anthony J Demetris7. 1. Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA. 2. Mount Sinai Kravis Children's Hospital and Recanati/Miller Transplantation Institute, Mount Sinai Health System, New York, NY. 3. Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, PA. 4. Section of Transplant Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI. 5. Institute of Liver Studies, King's College London, London, United Kingdom. 6. Rho, Inc., Chapel Hill, NC. 7. Department of Pathology, University of Pittsburgh, Pittsburgh, PA. 8. The Immune Tolerance Network, Bethesda, MD. 9. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California San Francisco, San Francisco, CA. 10. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, Pittsburgh, PA. 11. Siragusa Transplantation Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. 12. Transplantation Branch, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Rockville, MD. 13. Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. 14. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA. 15. Section of Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Houston, TX. 16. Department of Surgery, Duke University, Durham, NC. 17. Center for Liver Diseases and Transplantation, Department of Surgery, Columbia University Irving Medical Center, New York, NY. 18. Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases, Instituto de Salud Carlos III, Barcelona, Spain. 19. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Transplant and Regenerative Medicine Center, The Hospital for Sick Children, University of Toronto, Toronto, OH, Canada. 20. Liver Transplant Program, The Children's Hospital of Pennsylvania, Philadelphia, PA. 21. Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO. 22. Division of Gastroenterology, Hepatology, and Nutrition, Washington University School of Medicine, St. Louis, MO.
Abstract
BACKGROUND AND AIMS: Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. APPROACH AND RESULTS: We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. CONCLUSIONS: Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.
BACKGROUND AND AIMS: Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. APPROACH AND RESULTS: We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. CONCLUSIONS: Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.
Authors: Abraham Shaked; Bao-Li Loza; Elisabet Van Loon; Kim M Olthoff; Weihua Guan; Pamala A Jacobson; Andrew Zhu; Claire E Fishman; Hui Gao; William S Oetting; Ajay K Israni; Giuliano Testa; James Trotter; Goran Klintmalm; Maarten Naesens; Sumeet K Asrani; Brendan J Keating Journal: Nat Med Date: 2022-04-07 Impact factor: 87.241
Authors: Marco Romano; Raul Elgueta; Daniel McCluskey; Ana Maria Ortega-Prieto; Emilie Stolarczyk; Francesco Dazzi; Baltasar Lucendo-Villarin; Jose Meseguer-Ripolles; James Williams; Giorgia Fanelli; David C Hay; Fiona M Watt; Giovanna Lombardi Journal: Cells Date: 2021-12-22 Impact factor: 6.600