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 Foxp3 memory 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.

Long-Term Signs of T Cell and Myeloid Cell Activation After Intestinal Transplantation With Cellular Rejections Contributing to Further Increase of CD16+ Cell Subsets

“…The majority of the Tregs had a CCR4 + activated memory phenotype with co-expression of predominantly CCR6. Our results question the conclusions drawn from a recently published study in which high percentages of Tregs upon intestinal transplantation were ascribed to a special immunomodulatory protocol and associated with improved long-term graft function (45). In this study, ITx patients receiving the immunomodulatory protocol were compared to kidney transplant patient groups and healthy controls but not to ITx patients on other immunosuppressive medications.…”

Bortezomib for autoimmune hemolytic anemia after intestinal transplantation

“…The patient was pretreated with ATG and had bloodgroup AB+; CMV seropositive; 0/6 match for HLA‐A, B, and DR antigens. He received a per local protocol donor‐specific whole blood transfusion before the procedure . Immunosuppression included infliximab, basiliximab, tacrolimus, azathioprine, and prednisolone.…”

The role of osmotic self-inflatable tissue expanders in intestinal transplant candidates

“…Due to post-reperfusion edema the fascia could not be closed primarily but was closed four weeks later during a surgical re-exploration for a prolapsed ileostomy. The patient was administered a low-dose dual immunosuppressive regimen of tacrolimus and steroids [19]. No herniation or other skin-or fascia-related complications occurred and at last follow-up −7 years later-she was doing well.…”