干细胞移植在炎症性肠病治疗中的应用

随着干细胞和炎症性肠病(IBD)研究的深入,干细胞移植在IBD治疗中的应用取得一些进展。此文主要介绍了自体造血干细胞移植,同种异基因造血干细胞移植和间充质干细胞移植在IBD治疗中的应用。     

造血干细胞移植治疗炎症性肠病进展

炎症性肠病(IBD)是胃肠道慢性炎性肉芽肿性疾病,其发病与环境、遗传因素相关,传统治疗包括抗炎和抑制免疫等治疗.新近的研究提示造血干细胞移植(HSCT)治疗IBD有效,此文就HSCT治疗IBD的研究现状和存在的问题进行概述.     

干细胞治疗炎症性肠病的研究进展

炎症性肠病的患病人数在我国高速增长,传统药物治疗难以改变病程,且2/3的患者存在生物制剂失应答,亟需开发新疗法实现黏膜愈合。隐窝肠干细胞可分化成肠上皮细胞,并与肠上皮细胞协同修复肠道黏膜,维持肠道内稳态。炎症性肠病患者免疫功能紊乱,破坏肠道干细胞池自我更新,阻止黏膜修复再生导致黏膜屏障受损。近年来随着类器官共培养技术与单细胞测序技术的应用,免疫细胞与干细胞之间相关调控关系越加明确。干细胞移植有望重建黏膜屏障实现黏膜愈合,目前已开展多项干细胞临床研究并取得一定临床突破。本文综述免疫细胞与肠干细胞相关调控关系及干细胞临床研究前沿进展。     

生物学制剂和干细胞移植治疗炎症性肠病的进展

炎症性肠病（IBD）是一种病因复杂的肠道慢性炎症性疾病。治疗IBD的传统药物虽能控制症状,但多数患者反复发作迁延不愈。新近研究的生物学制剂、干细胞移植等疗法已逐渐用于临床,较传统药物凸显出一定的优势,成为近年来IBD治疗学的研究热点,该文就此两种新疗法进行概述。     

自体造血干细胞移植治疗难治性炎症性肠病10例回顾与随访

目的 回顾自体造血干细胞移植(HSCT)治疗10例炎症性肠病(IBD)患者的疗效及安全性.方法 2004年1月至2006年8月,采用HSCT治疗9例糖皮质激素及免疫抑制剂治疗无效的克罗恩病(CD)患者及1例Truelove临床重型溃疡性结肠炎(UC)患者.CD患者中2例CD活动指数(CDAD大于450(严重型),6例CDAI为150～450(活动型).1例UC患者为全结肠炎型.经环磷酰胺(CTX)及粒细胞刺激因子动员后,采集患者外周血于细胞,行CD34+细胞分选并置液氮保存,2周后行CTX及抗淋巴细胞球蛋白预处理,将解冻的干细胞回输.结果 HSCT后3和12个月时分别有5例和1例患者CDAI<150(完全缓解).2例术后CDAI分值下降但未达缓解标准;完全缓解者症状消失,血液检查指标正常,体重明显增加(5～20 kg).平均随访16.1个月,复发4例,除1例病情严重外,余均较术前病情减轻;5例患者获长期缓解.1例UC患者术后10个月无复发症状,血液检查指标均正常,但肠镜复查示无明显改善.与HSCT治疗相关的并发症有干细胞回输期间与白细胞减少相关的发热及感染、术后脱发,1例乙型肝炎病毒(HBV)携带者术后转氨酶水平及HBV-DNA滴度增高.结论 HSCT可改善其他方法治疗无效的难治性IBD,近期疗效满意,部分患者可获较长期的缓解,治疗期间无严重不良反应,但不能阻止病情复发,且不能改善患者肠道病理改变.     

造血干细胞移植与炎症性肠病

炎症性肠病(IBD)是病因未明的胃肠道慢性炎性肉芽肿性疾病，有终生复发倾向，重症患者迁延不愈，预后不良。传统治疗着眼于控制活动性炎症和调节免疫紊乱，常用的三类药物(水杨酸制剂、糖皮质激素和免疫抑制剂)对克罗恩病和溃疡性结肠炎的缓解率分别为70％与80％左右。长期使用上述药物又给患者带来难以克服的副作用，许多学者致力于寻找一种新的治疗途径。     

干细胞治疗在炎症性肠病中的研究进展

我国炎症性肠病(IBD)发病率近年来呈明显上升趋势,危重病例也逐渐增多。现有的IBD治疗主要着眼于控制活动性炎症和调节免疫紊乱,常用药物有5-氨基水杨酸类制剂、糖皮质激素、免疫抑制剂等,对危重及难治性病例疗效有限,且存在许多不良反应。干细胞移植治疗是一种新兴的治疗方法,也是近年来IBD治疗领域的研究热点之一。本文对既往干细胞移植治疗IBD的临床和基础研究进行回顾,着重介绍近年来该领域的新进展。     

基因工程化间充质干细胞移植治疗炎症性肠病的研究进展

炎症性肠病(IBD)是一类反复发作、难以治愈的肠道疾病.目前,医学上尚无治愈IBD的方法.间充质干细胞(MSC)移植可以改善IBD患者的症状,但由于其归巢效率较低,未达到预期的治疗效果.近年来,构建基因工程化MSC受到越来越多研究者的关注.MSC经外源基因修饰后可稳定表达这些基因,并使MSC迁移至损伤部位,发挥抗炎作用...     

炎症性肠病的治疗

炎症性肠病(IBD)的病因致今未明,因此缺乏特效治疗。溃疡性结肠炎(UC)与克隆病(CD)的治疗原则基本相同,但二者在近期疗效与防止复发方面则有区别,一般在UC优于CD.本病应以内科治疗为主,手术仅适用于UC有中毒性巨结肠经积     

干细胞疗法治疗炎症性肠病的应用

炎症性肠病是一种慢性炎症性疾病,主要包括克罗恩病和溃疡性结肠炎,其发病原因尚不清楚。干细胞疗法在治疗炎症性肠病方面可能是非常有价值的,近年来,干细胞疗法的研究也更加突出而显著,本文就干细胞疗法治疗炎症性肠病的应用作一概述。     

异基因造血干细胞移植治疗慢性粒细胞白血病长生存分析

目的:评价异基因造血干细胞移植(allo-HSCT)治疗慢性粒细胞白血病(CML)的疗效,并分析影响CML长生存的预后因素。方法:118例CML患者包括慢性期88例、加速期8例、急变期22例,其中83例接受相关移植、35例无关移植。预处理方案:36例患者用全身照射(TBI)联合环磷酰胺联合(Cy)、82例改良BuCy(白消安、环磷酰胺和阿糖胞苷)。移植物抗宿主病(GVHD)预防:68例相关人类白细胞抗原(HLA)全相合移植用环孢素(CsA)和甲氨蝶呤(MTX),50例无关供者及相关1个以上位点不合者采用CsA、MTX、抗胸腺细胞球蛋白(ATG)或麦考酚酸酯(MMF)。Cox模型分析影响长生存的因素。结果:118例患者除3例死于预处理相关毒性(RRT)外其余均获造血重建。移植后5年累计感染发生率为42.6%,巨细胞病毒血症累计阳性率为41.6%。Ⅱ～Ⅳ度急性GVHD累计发生率为33.3%,其中相关全相合供者(MSD)和无关、相关不相合供者(MRD/URD)发生率分别为23.1%和46.9%(P=0.01);1年累计慢性GVHD发生率为47.8%,其中MSD和MRD/URD慢性GVHD发生率分别为51.4%和42.2%(P=0.260)。GVHD致死率为18.3%。移植后5年白血病累计复发率为17%,其中MSD和MRD/URD复发率分别为12.5%和23.9%%(P=0.228)。5年累计总生存(OS)和无病生存(DSF)率分别为69.5%和62.6%,其中MSD与MRD/URD的5年OS率和DSF率分别为78.5%比57.2%和72.7%比48.3%(P=0.018,P=0.017)。慢性期与加速/急变期的5年OS率和DSF率分别79.9%、36.7%和72.4%、32.6%(P<0.001)。多因素Cox模型分析显示,Ⅱ～Ⅳ度急性GVHD、HLA不相合、诊断至移植时间≥1年为OS的独立危险因素。加速期、急变期和三联、四联GVHD预防方案为影响DSF的独立危险因素。结论:影响CML-allo-HSCT长生存的主要因素是移植的时机、疾病状态、HLA相合程度和移植后GVHD。GVHD是移植后死亡的主要原因。     

格列卫联合异基因造血干细胞移植治疗慢性粒细胞白血病

目的:为了考察格列卫联合异基因造血干细胞移植治疗慢性粒细胞白血病(CML)对移植及造血重建的影响。方法:对6例CML患者于移植前6周开始口服格列卫600~800mg/d至移植当日,预处理方案是福达拉宾、白消安、环磷酰胺,人类白细胞抗原(HLA)不相合者加用抗胸腺细胞球蛋白。移植物抗宿主病防治采用环孢素A加短程甲氨喋呤加霉酚酸酯。结果:6例全部成功植入,WBC>0.5×109·L-1平均为14.2d,PLT>20×109·L-1平均为15.6d。结论:CML患者移植前给予大剂量格列卫治疗不影响干细胞植入和骨髓造血的恢复。     

Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation

This study investigated the role of inflammatory cytokines in acute graft-versus-host disease (aGVHD) incidence and severity in 113 patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Among all tested cytokines in the first 3 months after allo-SCT, only interleukin-12 p70 (IL-12p70) levels in the first month were significantly associated with grades II to IV aGVHD development (P < .001). IL-12p70 levels were directly correlated with aGVHD severity grade (P < .001). Before aGVHD onset, blood monocytes, the main precursor pool of IL12p70-secreting dendritic cells, recovered more rapidly in patients with grades II to IV aGVHD (P = .005). Similarly, at the effector level, there was a more robust reconstitution of naive CD3+CD4+CD45RA+CD27+ T cells in patients developing grades II to IV aGVHD (P = .006). In multivariate analysis, IL-12p70 level measured in the first month was the strongest predictive factor for aGVHD development (P < .001). These findings, reconstituting a T(H)1 loop, support a model in which aGVHD reflects a type 1 alloreaction after RIC allo-SCT.     

Inflammatory bowel disease and liver transplantation for primary sclerosing cholangitis

OBJECTIVES: To compare the outcome of liver transplantation in primary sclerosing cholangitis (PSC) patients with and without inflammatory bowel disease (IBD), and to analyse the influence of the transplantation on the course of IBD. METHODS: Retrospective analysis of the data regarding PSC, IBD, and liver transplantation in all patients transplanted for PSC. SETTING: Single university transplantation centre. RESULTS: Thirty-one patients were transplanted for PSC, of whom 18 had IBD before liver transplantation. There were no differences in complication rate and outcome between patients with and patients without IBD. Before liver transplantation, the IBD course was active in three patients and quiescent in 14 patients (one patient was not evaluable). After liver transplantation, the course was active in five (one de-novo IBD) patients and quiescent in 13 patients. Exacerbations of IBD occurred in ten patients during treatment with steroids and a calcineurin blocker. Five patients with long-standing and extensive colitis developed colorectal neoplasia after liver transplantation (two colorectal cancer, two extensive dysplasia, one leiomyosarcoma). CONCLUSIONS: Concomitant IBD had no detrimental influence on the outcome of liver transplantation in patients with PSC. The course of IBD was not altered after liver transplantation. Immunosuppression including steroids did not prevent exacerbations of IBD. The development of colorectal neoplasia is a serious threat to patients with IBD and PSC after liver transplantation.     

Inflammatory bowel disease

These experiments have shown that the ability of sera, from patients with chronic ulcerative colitis (CUC) or granulomatous colitis (GC), to convey cytotoxicity for human colonic epithelial cells to normal peripheral blood lymphocytes in vitro seems to be a property of the IgM fraction, and that the antibody is cytophilic. Treatment of peripheral blood lymphocytes from patients with CUC or GC with goat antihuman whole serum proteins serum or antihuman IgM serum inhibited their cytotoxicity for human colonic epithelial cells, suggesting that a similar cytophilic antibody may be acting. These findings indicate that the cytotoxicity of lymphocytes for colonic cells involves an immune mechanism and, taken together with the results of previous studies, we have speculated that colonic bacteria, or their products, may be significant in the development of this cytotoxicity and in the pathogenesis of inflammatory bowel disease.Supported in part by NIH Grant AM 12808, USPHS.The authors wish to thank Mrs. V. Knopf for technical assistance; the volunteers whose collaboration made these experiments possible; and Mr. H. Brumfield for assistance with the analytic ultracentrifugation.