Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice.
Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice.
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DOI：
10.1097/mib.0000000000001273
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发表时间：
2017-11
影响因子：
4.9
通讯作者：
Sampson HA
中科院分区：
文献类型：
--
作者：
Dunkin D;Berin MC;Mondoulet L;Tobar S;Yeretssian G;Tordesillas L;Iuga A;Larcher T;Gillespie V;Benhamou PH;Colombel JF;Sampson HA
虽然炎症性肠病（IBD）在维持对肠道微生物群的耐受性方面失败，但很少有研究将免疫耐受用作IBD的治疗方法。我们假设在远端部位诱导免疫耐受可以通过旁观者调节过程抑制肠道炎症。通过使用Viaskin®贴片局部施用OVA 48小时诱导表皮耐受性。在一些实验中，使用单次喂入的OVA将表皮耐受性诱导的TdR驱动至肠。使用Foxp 3-DTR小鼠，使用针对TGF-β、IL-10和Treg消耗的中和抗体测试耐受性诱导的机制。在SAMP-YITFc小鼠中使用T细胞转移结肠炎、DSS结肠炎和回肠炎测试皮肤引流TdR或表皮耐受性预防或治疗实验性IBD的能力。评估体重减轻、结肠炎性细胞因子和组织学。表皮暴露于OVA通过TGF-β依赖性但IL-10和iFoxp 3 + Treg非依赖性机制诱导全身免疫耐受。皮肤引流TdR抑制结肠炎的发展。对模型抗原的表皮耐受性防止了DSS和SAMP-YITFc模型中的肠道炎症，并且重要的是可以阻止在结肠炎的T细胞转移模型中已经经历体重减轻的小鼠的疾病。这伴随着在结肠中显著积累的Foxp 3+和Foxp 3 + T细胞。这是第一次证明对模型抗原的表皮耐受可以导致炎症的旁观者抑制和IBD临床前模型中疾病进展的预防。
Although inflammatory bowel disease (IBD) is a failure in maintaining tolerance to the intestinal microbiota, few studies have investigated the use of immunologic tolerance as a treatment approach for IBD. We hypothesized that induction of immune tolerance at a distal site could suppress intestinal inflammation through a process of bystander regulation. Epicutaneous tolerance was induced by topical application of OVA using a Viaskin® patch for 48 h. In some experiments, a single feed of OVA was used to drive epicutaneous tolerance-induced Tregs to the intestine. The mechanism of tolerance induction was tested using neutralizing antibodies against TGF-β, IL-10, and Treg depletion using Foxp3-DTR mice. The capacity of skin-draining Tregs, or epicutaneous tolerance, to prevent or treat experimental IBD was tested using T cell transfer colitis, DSS colitis, and ileitis in SAMP-YITFc mice. Weight loss, colonic inflammatory cytokines and histology were assessed. Epicutaneous exposure to OVA induced systemic immune tolerance by a TGF-β-dependent, but IL-10 and iFoxp3+ Treg-independent mechanism. Skin draining Tregs suppressed the development of colitis. Epicutaneous tolerance to a model antigen prevented intestinal inflammation in the DSS and SAMP-YITFc models, and importantly could halt disease in mice already experiencing weight loss in the T cell transfer model of colitis. This was accompanied by a significant accumulation of LAP+ and Foxp3+ Tregs in the colon. This is the first demonstration that epicutaneous tolerance to a model antigen can lead to bystander suppression of inflammation and prevention of disease progression in preclinical models of IBD.