title: The Leuven Immunomodulatory Protocol Promotes T-Regulatory Cells and Substantially Prolongs Survival After First Intestinal Transplantation.
abstract: Intestinal transplantation (ITx) remains challenged by frequent/severe rejections and immunosuppression-related complications (infections/malignancies/drug toxicity). We developed the Leuven Immunomodulatory Protocol (LIP) in the lab and translated it to the clinics. LIP consists of experimentally proven maneuvers, destined to promote T-regulatory (Tregs)-dependent graft-protective mechanisms: donor-specific blood transfusion (DSBT); avoiding high-dose steroids/calcineurin-inhibitors; and minimizing reperfusion injury and endotoxin translocation. LIP was tested in 13 consecutive ITx from deceased donors (2000-2014) (observational cohort study). Recipient age was 37 years (2.8-57 years). Five-year graft/patient survival was 92%. One patient died at 9 months due to aspergillosis, another at 12 years due to nonsteroidal anti-inflammatory drug-induced enteropathy. Early acute rejection (AR) developed in two (15%); late AR in three (23%); all were reversible. No chronic rejection (CR) occurred. No malignancies developed and estimated glomerular filtration rate remained stable post-Tx. At last follow-up (3.5 years [0.5-12.5 years]), no donor-specific antibodies were detected and 11 survivors were total parenteral nutrition free with a Karnofsky score >90% in 8 recipients (follow-up >1 years). A high frequency of circulating CD4+CD45RA-Foxp3himemory Tregs was found (1.8% [1.39-2.21]), comparable to tolerant kidney transplant (KTx) recipients and superior to stable immunosuppression (IS)-KTx, KTx with CR, and healthy volunteers. In this ITx cohort we show that DSBT in a low-inflammatory/pro-regulatory environment activates Tregs at levels similar to tolerant-KTx, without causing sensitization. LIP limits rejection under reduced IS and thereby prolongs long-term survival to an extent not previously attained after ITx.
authors.affiliation: Abdominal Transplant Surgery & Transplant Coordination, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: L J
authors.initials: LJ
authors.lastname: Ceulemans
authors.affiliation: Institut de Recherche en Transplantation, Urologie et Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, University of Nantes, Nantes, France.
authors.forename: F
authors.initials: F
authors.lastname: Braza
authors.affiliation: Abdominal Transplant Surgery & Transplant Coordination, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Monbaliu
authors.affiliation: Abdominal Transplant Surgery & Transplant Coordination, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Jochmans
authors.affiliation: Translational Cell and Tissue Research, University Hospitals Leuven, and Department of Imaging and Pathology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: De Hertogh
authors.affiliation: Division of Hepatology, University Hospitals Leuven, and Department of Clinical and Experimental Medicine, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Du Plessis
authors.affiliation: Laboratory for Histocompatibility and Immunogenetics (HILA), Red Cross Flanders, Mechelen, Belgium.|Experimental Transplantation, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: M-P
authors.initials: MP
authors.lastname: Emonds
authors.affiliation: Experimental Transplantation, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Kitade
authors.affiliation: Experimental Transplantation, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Kawai
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Experimental Transplantation, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.|Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Koshiba
authors.affiliation: Experimental Transplantation, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Sprangers
authors.affiliation: Institut de Recherche en Transplantation, Urologie et Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, University of Nantes, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Brouard
authors.affiliation: Experimental Transplantation, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Waer
authors.affiliation: Abdominal Transplant Surgery & Transplant Coordination, University Hospitals Leuven, and Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Pirenne
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D001803:Blood Transfusion; D015331:Cohort Studies; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007165:Immunosuppression Therapy; D007410:Intestinal Diseases / Q000601:surgery; D007422:Intestines / Q000637:transplantation; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D002985:Clinical Protocols
keywords: T cell biology; clinical research/practice; immune regulation; intestinal disease; intestine/multivisceral transplantation; tolerance: clinical; translational research/science