Abstract
Background Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). However, CNI toxicity leads to significant morbidity. Moreover, CNIs cannot prevent long-term allograft injury. Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties, which may promote allograft tolerance and ameliorate toxicity of high-dose CNI. The MYSTEP1 trial aims to investigate safety and feasibility of donor-derived MSCs in pLT. Methods/Design 7 to 10 children undergoing living-donor pLT will be included in this open-label, prospective pilot trial. A dose of 1 × 106 MSCs/kg body weight will be given at two time points: first by intraportal infusion intraoperatively and second by intravenous infusion on postoperative day 2. In addition, participants will receive standard immunosuppressive treatment. Our primary objective is to assess the safety of intraportal and intravenous MSC infusion in pLT recipients. Our secondary objective is to evaluate efficacy of MSC treatment as measured by the individual need for immunosuppression and the incidence of biopsy-proven acute rejection. We will perform detailed immune monitoring to investigate immunomodulatory effects. Discussion Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival.
Highlights
Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation
Introduction of current standard immunosuppressive therapies including CNIs has had a major impact on reduction of acute mortality after pediatric liver transplantation [2, 50]
These limitations motivate our search for alternative cellular treatment strategies for achieving allograft tolerance after pediatric liver transplantation
Summary
Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival. Long-term continuous exposure to immunosuppressive drugs, such as CNIs, mTOR inhibitors, and steroids, carries with it significant clinical side effects. These include renal dysfunction, arterial hypertension, glucose intolerance, posttransplant lymphoproliferative disorder, and opportunistic infections [4, 5]. CNIs are not effective in preventing chronic de novo hepatitis in transplanted allografts This long-term graft injury is associated with a high risk of developing progressive graft fibrosis after 10 years, and up to 25% of patients need retransplantation [9]. We need novel immunomodulating approaches to limit the risk of immunosuppressive therapy while continuously improving outcome, achieving optimal cognitive and physical development, and maintaining a high quality of life for liver-transplanted children
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