Van den Brande Jan M H, Koehler Tamara C, Zelinkova Zuzana, Bennink Roelof J, te Velde Anje A, ten Cate Fibo J W, van Deventer Sander J H, Peppelenbosch Maikel P, Hommes Daniël W
Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Gut. 2007 Apr;56(4):509-17. doi: 10.1136/gut.2006.105379. Epub 2006 Nov 2.
The human anti-tumour necrosis factor (TNF) antibody infliximab binds to the membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes in patients with Crohn's disease in vitro.
To test whether the ability of rapid anti-TNF-induced apoptosis in the gut predicts the efficacy of anti-TNF treatment in inflammatory bowel disease.
(99m)Technetium-annexin V single-photon emission computer tomography (SPECT) was performed in 2 models of murine experimental colitis and in 14 patients with active Crohn's disease as assessed by the Crohńs Disease Activity Index (CDAI) to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. Disease activity was evaluated 2 weeks after infliximab infusion using the CDAI (definition response: drop of >100 points).
Colonic uptake of (99m)Tc-annexin V significantly increased in 2,4,6-trinitrobenzene sulphonate-induced colitis as well as in transfer colitis on administration of anti-TNF antibodies compared with a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of (99m)Tc-annexin V significantly increased in patients with active Crohn's disease responding to infliximab treatment. Colonic (99m)Tc-annexin V uptake ratio (mean (SEM)) increased from 0.24 (0.03) to 0.41(0.07) (p<0.01), 24 h after infliximab infusion (5 mg/kg). A mean increase of 98.7% in colonic uptake of (99m)Tc-annexin V could be detected in 10 of the 14 responding patients (CDAI >100 points at week 2) compared with 15.2% in non-responding patients (p = 0.03). Analysis of the mucosal biopsy specimens identified lamina propria T cells as target cells undergoing apoptosis.
These in vivo observations support the notion that colonic uptake of (99m)Tc-annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.
人抗肿瘤坏死因子（TNF）抗体英夫利昔单抗可与膜TNF结合，随后在体外诱导克罗恩病患者活化的固有层T淋巴细胞凋亡。
检测肠道中抗TNF快速诱导凋亡的能力是否可预测抗TNF治疗在炎症性肠病中的疗效。
采用锝-99m标记的膜联蛋白V单光子发射计算机断层扫描（SPECT）技术，对2种小鼠实验性结肠炎模型和14例经克罗恩病活动指数（CDAI）评估为活动期的克罗恩病患者进行研究，以观察抗TNF治疗对活动期结肠炎时肠道细胞凋亡的影响。在英夫利昔单抗输注2周后，使用CDAI评估疾病活动度（定义缓解：下降超过100分）。
与对照抗体相比，在2,4,6-三硝基苯磺酸诱导的结肠炎以及转移结肠炎模型中，给予抗TNF抗体后，锝-99m标记的膜联蛋白V在结肠的摄取显著增加，这是通过专用动物针孔SPECT测定的。此外，在对英夫利昔单抗治疗有反应的活动期克罗恩病患者中，锝-99m标记的膜联蛋白V摄取也显著增加。英夫利昔单抗输注（5mg/kg）24小时后，结肠锝-99m标记的膜联蛋白V摄取率（均值（标准误））从0.24（0.03）增至0.41（0.07）（p<0.01）。在14例有反应的患者中，10例（第2周时CDAI下降>100分）结肠锝-99m标记的膜联蛋白V摄取平均增加98.7%，而无反应患者仅增加15.2%（p = 0.03）。对黏膜活检标本的分析确定固有层T细胞为发生凋亡的靶细胞。
这些体内观察结果支持以下观点，即结肠摄取锝-99m标记的膜联蛋白V与抗TNF治疗的临床获益相关，可能可预测治疗成功。
