Organ transplantation is the only definite treatment of many critical diseases of the liver, kidney, heart, pancreas and lung. Although it is the primary therapeutic option at present, transplanted patients have to deal with the numerous side effects of life-long dependence on immunosuppressive drugs, whereas at the same time these drugs fail to prevent chronic rejection in many cases. The risk of developing cancer and opportunistic infections is also markedly increased in solid organ transplant recipients receiving long-term immunosuppressive therapy. Cancer and opportunistic infections cannot be fully avoided, since they result from the desired immunosuppressive effect that affects not only the anti-graft response, but the entire immune response. Finding a way to establish donor-specific immunological tolerance without the need for non-specific immunosuppression remains one of the major goals in transplantation medicine.

Mesenchymal stem cells (MSC) are multipotent progenitors within the bone marrow capable of differentiating into various cells and tissues, such as chondrocytes, osteoblasts and adipocytes. MSC can be isolated after ex vivo culture of the adherent mononuclear bone marrow cell fraction. After ex vivo expansion, human MSC have a fibroblastic-like morphology, and are uniformly positive for SH2, SH3, CD29, CD44, CD71, CD90, CD105, CD106, CD120a, CD124, and CD166 but are negative for common hematopoietic markers like CD14, CD45 or CD34. Human MSC express HLA-class I and can be induced to express HLA-class II by IFN-γ. However, MSC failed to induce proliferation of allogeneic T-cells in in-vitro co-culture experiments. Further, MSC can escape lysis from both cytotoxic T-cells and KIR-mismatched NK cells.

MSC directly suppress ongoing immune response through several mechanisms and thus demonstrate a wide-ranging potential for the development of tolerogenic strategies after transplantation. In a few attempts, the use of MSC in solid organ transplantation has been examined in animals. Under particular conditions, MSC were shown to prolong the survival of skin and liver transplants in primate and rats models. Controversial results were observed in a rat heart transplantation model due to different timing of MSC application as well as cumulative number of cells administered. In addition to their potential immunosuppressive effects, the potential beneficial effects of MSC on ischemia/reperfusion injury have been investigated in animal models of kidney ischemia. In liver diseases, it was also suggested that MSC administration could help liver regeneration in animal models of terminal liver failure or metabolic diseases. These potential beneficial effects of MSC administration on the liver and the kidney have not been tested and/or confirmed in clinical settings, but no renal or hepatic deleterious effect of MSC administration has been described so far either in animal or in human trials. Indeed, a possible effect of MSC on organ transplant survival remains questionable, and justifies further investigation. Four clinical trials (phase I-II) are now investigating the safety and the feasiblility of autologous MSC administration in patients with renal allograft transplants (www.ClinicalTrials.gov). Clinical trials of MSC in patients undergoing solid organ transplantation may confirm the potential of these cells to provide a valuable tool in transplantation medicine. 

BackgroundInclusion

1. Liver and kidney recipients Inclusion criteriaMale or female patients between 18 and 75 years of age, who will undergo first KT or whole LT from a cadaveric (DBD or DCD) organ donor; fertile female patients must use a reliable contraception method; Informed consent given by patient, for the complete (MSC + follow-up) or partial (no MSC + follow-up) studySuccessful liver or kidney transplantation, with demonstration of organ function (improvement of INR in liver recipients and of creatinine in kidney recipients) at 24-36h and normal graft vasculature at Doppler examinationExclusion criteria Past history of malignant disease in organ donor or recipient, with the exception of hepatocarcinoma within the Milan criteria for the LT patients Active uncontrolled infection (recipient and organ donor)HIV or HCV positive (recipient or the organ donor)EBV-negative recipientRetransplantationCombined transplantationLiving related transplantation or split liver transplantationAutoimmune disease or expected impossibility to wean immunosuppression (LT) or corticosteroids (KT) (recipient)Endotracheal intubation (recipient)Postoperative cardiovascular instability, active hemorrhage, or any other serious clinical complication between transplantation and evaluation for suitability for MSC infusion (recipient)For KT recipient: Panel reactive antibodies (PRA) >50% (recipient) 2. MSC donors Inclusion criteriaUnrelated to the graft donor or recipientMale or femaleAge > 18 yrsNo HLA matching requiredFulfills generally accepted criteria for allogeneic HSC donationInformed consent given by donorExclusion criteriaAny condition not fulfilling inclusion criteriaKnown allergy to lidocaineAny risk factor for transmissible infectious diseases, in particular HIV

-First LT recipient was included in early 2012, inclusion should be completed in late 2013, 6 months results in spring 2014

-First KT recipient included in summer 2013

INFUSION OF THIRD-PARTY MESENCHYMAL STEM CELLS (MSC) AFTER KIDNEY AND LIVER TRANSPLANTATION:

A PHASE I-II, OPEN-LABEL, CLINICAL STUDY (EudraCT 2011-001822-81 & NCT01429038)

O. Detry 1, MH Delbouille 1, C Lechanteur 2, J Somja 3, A Deroover 1, L Weekers 4, JP Squifflet 1, P Honore 1, P Delvenne 3, M Meurisse 1, E Baudoux 2, Y Beguin 2

1 Dpt of Abdominal Surgery and Transplantation; 2 Dpt of Hematology; 3 Dpt of Pathology, 4 Dpt of Nephrology

CHU Liège, Sart Tilman B35, University of Liège, Liège, Wallonia, Belgium Email: olivier.detry@transplantation.be

The present project aims at evaluating the safety and tolerability of third party MSC administration after liver or kidney organ transplantation.

This study is a monocentric, open-label, prospective phase I-II study, including 20 liver and 20 kidney transplant recipients.  In a first step, after successful transplantation, 10 liver and 10 kidney transplant recipients under standard immunosuppression (TAC-MMF-steroids + anti-IL2 antibodies for the KT patients) will receive an intravenous infusion of third party (healthy volunteers) MSC at a dose of 1.5-3.0 x106/kg on postoperative day 3 2. Except for the collection, expansion and infusion of MSC, the clinical management of the patients will not differ from that of routine transplantation.  In a second step, in all KT patients without rejection and with normal creatinin and graft biopsy, steroid weaning will be performed at month 3.  In LT patients without rejection episode and with normal graft function and graft biopsy, weaning of immunosuppression will be attempted at month 6; TAC will be progressively tapered from month 6 to be stopped at month 9, and if the patient did not develop rejection, MMF will be tapered from month 9 to be stopped at month 12.  The 20 study patients will be compared to a control group of patients (10 liver and 10 kidney transplant recipients) that will be selected with the same criteria that the study patients, but who refused to be included in the study group while accepting the supplementary blood collection necessary for the immunological comparison between the two groups.

PrimaryTo evaluate the safety of MSC infusion after liver and kidney transplantation: 1. infusional toxicity;2. incidence of infections (bacterial, viral, fungal, parasitic) and cancers (PTLD, others) at 6 months Secondary1. to evaluate patient and graft survivals;2. to evaluate the effects of MSC on graft function (for LT: bilirubin, INR, transaminases, GGT, at day 7, months 1, 3, 6, 9, 12; in KT: number of post transplant hemodialysis, creatinine at day 7, months 1, 3, 6, 9, 12);3. to evaluate biopsy-proven (Banff classification) rejection rates at months 3, 6, 9, 12; 4; to evaluate the feasibility and safety of weaning or decreasing immunosuppression;5. to evaluate recipient’s immune function (T cell blood populations (including T regs) by FACS, TREC quantification, Vβ repertoire diversity, pathogen-specific T cells, anti-organ donor HLA antibodies) at months 1, 2, 3, 4, 6, 9, 12;6. to evaluate the potential development of anti-MSC donor HLA antibodies at months 1, 3, 6, 12;

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