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.
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.
J Crohns Colitis. 2015 Dec;9(12):1071-8. doi: 10.1093/ecco-jcc/jjv144. Epub 2015 Aug 24.
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.
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.
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%].
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].
体外生成的自体免疫耐受树突状细胞（tolDCs）可恢复实验性结肠炎中的免疫耐受。本研究旨在确定自体 tolDC 在难治性克罗恩病（CD）患者中的安全性和耐受性。
设计了一项 I 期、单中心、序贯队列、剂量范围研究。按照先前开发的方案，从单核细胞体外生成稳定的 tolDCs，并通过超声引导腹腔内注射给药。建立了 6 个连续的难治性 CD 队列：前 3 个队列分别以递增剂量（2×10（6）/5×10（6）/10×10（6））单次腹腔内注射 tolDCs；后 3 个队列以相同递增剂量接受 3 次双周腹腔内注射。连续评估安全性。患者从第 0 周至 12 周进行评估，并随访 1 年以评估安全性。
纳入 9 例患者。tolDC 注射或随访期间未检测到不良反应。3 例患者因 CD 加重而退出研究。克罗恩病活动指数（CDAI）从 274[60]（均值（标准差[SD]））降至 222[113]（p=0.3）；1 例（11%）患者达到临床缓解（CDAI＜150），2 例（22%）达到临床应答（CDAI 下降≥100）。克罗恩病内镜严重程度指数（CDEIS）从 18[5]降至 13[8]（p=0.4）；3 例（33%）患者病变明显改善。生活质量（炎症性肠病问卷[IBDQ]）从 125[27]增加至 131[38]（p=0.7）；1 例（11%）患者在第 12 周达到缓解（IBDQ≥170），2 例（22%）达到应答（IBDQ 评分增加≥16）。
腹腔内给予自体 tolDC 在难治性 CD 患者中似乎是安全且可行的。应开展进一步的研究以检验临床获益、确定最佳给药途径和剂量，并监测免疫反应；参见[www.eudract.ema.europa.eu，EudraCT 编号 2007-003469-42；www.aemps.gob.es 编号 PEI 08-049]。
