title: Intraperitoneal Administration of Autologous Tolerogenic Dendritic Cells for Refractory Crohn's Disease: A Phase I Study.
abstract: OBJECTIVE
  Ex vivo-generated autologous tolerogenic dendritic cells [tolDCs] can restore immune tolerance in experimental colitis. The aim of this study was to determine the safety and tolerability of administration of autologous tolDCs in refractory Crohn's disease [CD] patients.
  
  
  METHODS
  A phase-I, single-centre, sequential-cohorts, dose-range study was designed. Stable tolDCs were generated ex vivo from monocytes following a previously developed protocol, and administered by sonography-guided intraperitoneal injection. Six sequential refractory-CD cohorts were established: the first three cohorts received a single intraperitoneal injection of tolDCs at escalating doses [2 x 10(6)/5 x 10(6)/10 x 10(6)]; and the last three cohorts received three biweekly intraperitoneal injections at same escalating doses. Safety was sequentially evaluated. Patients were assessed from week 0 to 12 and followed up for 1-year period for safety.
  
  
  RESULTS
  Nine patients were included. No adverse effects were detected during tolDC injection or follow-up. Three patients withdrew from the study due to CD worsening. Crohn's Disease Activity Index [CDAI] decreased from 274 [60] {mean (standard deviation [SD])} to 222 [113] [p = 0.3]; one [11%] patient reached clinical remission [CDAI < 150] and two [22%] clinical response [CDAI decrease ≥ 100]. Crohn's Disease Endoscopic Index of Severity [CDEIS] decreased from 18 [5] to 13 [8] [p = 0.4]; lesions improved markedly in three patients [33%]. Quality of life (inflammatory bowel disease questionnaire [IBDQ]) changed from 125 [27] to 131 [38] [p = 0.7]; remission [IBDQ at Week 12 ≥ 170] was reached in one [11%] case and response [IBDQ score increase ≥ 16] in two [22%].
  
  
  CONCLUSIONS
  Intraperitoneal administration of autologous tolDCs appears safe and feasible in refractory CD patients. Further studies should be developed to test clinical benefit, determine the optimal administration route and dose, and monitor the immune responses; See [www.eudract.ema.europa.eu, EudraCT number 2007-003469-42; www.aemps.gob.es number PEI 08-049].
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Aranzazu
authors: A
authors: Jauregui-Amezaga
authors: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain Fundació Clínic, Hospital Clínic de Barcelona and Centre Esther Koplowitz, Barcelona, Spain.
authors: Raquel
authors: R
authors: Cabezón
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Anna
authors: A
authors: Ramírez-Morros
authors: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain Fundació Clínic, Hospital Clínic de Barcelona and Centre Esther Koplowitz, Barcelona, Spain.
authors: Carolina
authors: C
authors: España
authors: Radiology Department, Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Jordi
authors: J
authors: Rimola
authors: Radiology Department, Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Concepció
authors: C
authors: Bru
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Susana
authors: S
authors: Pinó-Donnay
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Marta
authors: M
authors: Gallego
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Maria Carme
authors: MC
authors: Masamunt
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Ingrid
authors: I
authors: Ordás
authors: Hemotherapy and Hemostasis Department, Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Miguel
authors: M
authors: Lozano
authors: Hemotherapy and Hemostasis Department, Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Joan
authors: J
authors: Cid
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Julian
authors: J
authors: Panés
authors: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Daniel
authors: D
authors: Benítez-Ribas
authors: Gastroenterology Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERhed], Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Elena
authors: E
authors: Ricart
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003424:Crohn Disease / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000637:transplantation*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D008875:Middle Aged; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult
keywords: Cell therapy; immune-mediated diseases; inflammatory bowel diseases