Combinations of anti-GITR antibody and CD28 superagonist ameliorated dextran sodium sulfate-induced mouse colitis
Combinations of anti-GITR antibody and CD28 superagonist ameliorated dextran sodium sulfate-induced mouse colitis
复制标题
DOI：
10.1093/cei/uxac039
复制
发表时间：
2022-05-03
影响因子：
4.6
通讯作者：
Li，Xiao-Kang
中科院分区：
文献类型：
--
作者：
Ma，Kuai;Que，Weitao;Li，Xiao-Kang
溃疡性结肠炎（UC）是炎症性肠病（IBD）的两种主要形式之一，是一种病因不明的结肠黏膜特发性慢性炎症性疾病。据报道，白细胞介素(IL)-10在维持肠道环境中的免疫稳态中起着至关重要的作用。1型调节性T （Tr1）细胞是CD4+Foxp3−T细胞的一个亚群，能够分泌大量具有有效免疫抑制特性的IL-10。在本研究中，我们发现抗gitr抗体（G3c）和CD28超级激动剂（D665）联合处理刺激了大量Tr1细胞的产生。此外，G3c/D665治疗不仅能显著缓解严重的粘膜损伤，还能降低结肠缩短、体重减轻和便血的发生率。右旋糖酐硫酸钠（DSS）上调脾淋巴细胞（SPLs）和结肠组织中IL-6、IL-1β、IL-17、IL-12、肿瘤坏死因子- α、C-C趋化因子受体5型和Bax的mRNA水平，而G3c/D665则相反抑制这些基因的mRNA水平升高。此外，G3c/D665治疗改变了SPLs、肠系膜淋巴结（MLNs）和固有层淋巴细胞（LPLs）中CD4+和CD8+T细胞的比例，并增加了CD4+CD25+Foxp3+调节性T细胞。因此，G3c和D665联合治疗通过在体内通过肌筋膜纤维肉瘤途径诱导大量Tr1细胞生成，并全身和局部减轻炎症反应，对dss诱导的小鼠UC有效。
Ulcerative colitis (UC) is one of the two main forms of inflammatory bowel disease (IBD) and is an idiopathic, chronic inflammatory disease of the colonic mucosa with an unclear etiology. Interleukin (IL)-10 has been reported to play a crucial role in the maintenance of immune homeostasis in the intestinal environment. Type 1 regulatory T (Tr1) cells are a subset of CD4+Foxp3−T cells able to secrete high amounts of IL-10 with potent immunosuppressive properties. In this study, we found that the combination of anti-GITR antibody (G3c) and CD28 superagonist (D665) treatment stimulated the generation of a large amount of Tr1 cells. Furthermore, G3c/D665 treatment not only significantly relieved severe mucosal damage but also reduced the incidence of colonic shortening, weight loss, and hematochezia. Dextran sodium sulfate (DSS) upregulated the mRNA levels of IL-6, IL-1β, IL-17, IL-12, tumor necrosis factor-alpha, C-C chemokine receptor type 5, and Bax in splenic lymphocytes (SPLs) and colon tissues, while G3c/D665 treatment conversely inhibited the increase in mRNA levels of these genes. In addition, G3c/D665 treatment altered the proportion of CD4+and CD8+T cells and increased CD4+CD25+Foxp3+regulatory T cells in SPLs, mesenteric lymph nodes (MLNs), and lamina propria lymphocytes (LPLs). Thus, the combination of G3c and D665 treatment showed efficacy against DSS-induced UC in mice by inducing a large amount of Tr1 cell generation via the musculoaponeurotic fibrosarcoma pathwaysin vivoand relieving inflammatory responses both systematically and locally.