Objective External fistulas represent a disabling manifestation of Crohn's disease with a difficult curability and a high relapse rate despite a large therapeutic armamentarium. Stem cell therapy is a novel and promising approach for treatment of chronic inflammatory conditions. We therefore investigated the feasibility, safety and efficacy of serial intrafistular injections of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in the treatment of fistulising Crohn's disease.
Patients and methods We enrolled 12 consecutive outpatients (eight males, median age 32 years) refractory to or unsuitable for current available therapies. MSCs were isolated from bone marrow and expanded ex vivo to be used for both therapeutic and experimental purposes. Ten patients (two refused) received intrafistular MSC injections (median 4) scheduled every 4 weeks, and were monitored by surgical, MRI and endoscopic evaluation for 12 months afterwards. The feasibility of obtaining at least 50×106 MSCs from each patient, the appearance of adverse events, and the efficacy in terms of fistula healing and reduction of both Crohn's disease and perianal disease activity indexes were evaluated. In addition, the percentage of both mucosal and circulating regulatory T cells expressing FoxP3, and the ability of MSCs to influence mucosal T cell apoptosis were investigated.
Results MSC expansion was successful in all cases; sustained complete closure (seven cases) or incomplete closure (three cases) of fistula tracks with a parallel reduction of Crohn's disease and perianal disease activity indexes (p<0.01 for both), and rectal mucosal healing were induced by treatment without any adverse effects. The percentage of mucosal and circulating regulatory T cells significantly increased during the treatment and remained stable until the end of follow up (p<0.0001 and p<0.01, respectively). Furthermore, MSCs have been proven to affect mucosal T cell apoptotic rate.
Conclusions Locally injected MSCs represent a feasible, safe and beneficial therapy in refractory fistulising Crohn's disease.
- Crohn's disease fistulas
- mesenchymal stromal cells
- regulatory T cells
- crohn's disease
- stem cells
- T lymphocytes
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FL and GRC equally contributed to this manuscript.
Funding This study was financed in part by grants from: Istituto Superiore di Sanità (National Program on Stem Cells), European Union (FP6 program ALLOSTEM), Ministero dell'Istruzione, dell'Università e della Ricerca (Progetti di Rilevante Interesse Nazionale), Regione Lombardia (Research Project: “Trapianto di cellule staminali adulte per scopi di terapia cellulare sostitutiva, riparativa e rigenerativa”), and Fondazione CARIPLO to FL; by Fondazione IRCCS Policlinico San Matteo (Progetti di Ricerca Corrente) to RC, RM, FL and GRC; by Ministero dell'Istruzione, dell'Università e della Ricerca (Progetti di Rilevante Interesse Nazionale) to RC and GRC; by Istituto Superiore di Sanità (ISS per Alleanza contro il Cancro: Programma Straordinario di Ricerca Oncologica 2006), Ministero della Salute (Progetto Ricerca Finalizzata ICS 030.4 RF 2005/07) to RM; and by Associazione Italiana Ricerca sul Cancro (AIRC) to MEB.
Competing interests None.
Ethics approval This study was conducted with the approval of the Bio-Ethics Committee of IRCCS Policlinico San Matteo Foundation, Pavia.
Provenance and peer review Not commissioned; externally peer reviewed.