Activated glycoprotein A repetitions predominant (GARP)-expressing regulatory T cells inhibit allergen-induced intestinal inflammation in humanized mice
Activated glycoprotein A repetitions predominant (GARP)-expressing regulatory T cells inhibit allergen-induced intestinal inflammation in humanized mice
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DOI：
10.1016/j.jaci.2015.04.020
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发表时间：
2015-07-01
影响因子：
14.2
通讯作者：
Bellinghausen, Iris
中科院分区：
文献类型：
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作者：
Eschborn, Melanie;Weigmann, Benno;Bellinghausen, Iris
工作背景：最近，我们在PBMC移植的免疫缺陷小鼠中建立了过敏原诱导的IgE依赖性肠道炎症的人源化小鼠模型。目的：在本研究中，我们想研究调节性T（Treg）细胞及其活化状态在该模型中的作用。非肥胖型糖尿病-重度联合免疫缺陷-γ c（-/-）在存在或不存在不同浓度的CD 4（+）CD 25（+）的情况下，向小鼠腹腔内注射来自过敏供体的人PBMC以及相应的过敏原或NaCl作为对照。同一个供体的Treg细胞。在1周后额外的过敏原加强后，在第21天用过敏原直肠攻击小鼠，并通过高分辨率视频微型内窥镜系统监测肠道炎症，评估透明度、粒度、纤维蛋白产生、血管分布和粪便。小鼠血清中的变应原特异性人IgE，仅在PBMC+变应原处理的小鼠中可检测到，通过以至少1：10的比例共注射Treg细胞强烈抑制。因此，Treg细胞的存在显着减少了直肠过敏原激发后IgE依赖性过敏原诱导的肠道炎症。此外，Treg细胞在体外减少了回收的人CD 4（+）T细胞的过敏原特异性增殖和细胞因子产生。注射前Treg细胞的活化进一步增加了所有抑制作用。肠道炎症的预防也发生了糖蛋白A的重复为主，一种分子表达的活化调节性T细胞，而它的封锁完全废除抑制调节性T细胞的管理。这些结果表明，人PBMC移植小鼠中的过敏原特异性肠道炎症可以通过增强自体Treg细胞的数量或活性来避免，其对于肠变应性疾病的治疗干预具有很大的意义。
Background: Recently, we developed a humanized mouse model of allergen-induced IgE-dependent gut inflammation in PBMC-engrafted immunodeficient mice.Objective: In the present study, we wanted to investigate the role of regulatory T (Treg) cells and their activation status in this model.Methods: Nonobese diabetic-severe combined immunodeficiency-gamma c(-/-) mice were injected intraperitoneally with human PBMCs from allergic donors together with the respective allergen or NaCl as control in the presence or absence of different concentrations of CD4(+) CD25(+) Treg cells of the same donor. After an additional allergen boost 1 week later, mice were challenged with the allergen rectally on day 21 and gut inflammation was monitored by a high-resolution video mini-endoscopic system evaluating translucency, granularity, fibrin production, vascularity, and stool.Results: Allergen-specific human IgE in mouse sera, which was detectable only in PBMC plus allergen-treated mice, was strongly inhibited by coinjection of Treg cells at a ratio of at least 1:10. Consequently, the presence of Treg cells significantly decreased IgE-dependent allergen-induced gut inflammation after rectal allergen challenge. In addition, Treg cells reduced allergen-specific proliferation and cytokine production of recovered human CD4(+) T cells in vitro. Activation of Treg cells before injection further increased all inhibitory effects. Prevention of gut inflammation also occurred by the administration of glycoprotein A repetitions predominant, a molecule expressed by activated Treg cells, whereas its blockade completely abrogated inhibition by Treg cells.Conclusions: These results demonstrate that allergen-specific gut inflammation in human PBMC-engrafted mice can be avoided by enhancing the numbers or activity of autologous Treg cells, which is of great interest for therapeutic intervention of allergic diseases of the intestine.