Background

Integrin αvβ6 can convert the transforming growth factor (TGF)-β precursor to the mature form. Resiquimod (R848) can generate TGF-β-producing regulatory T cells (Treg). Thus, to concurrent administration of specific antigen and R848 may generate antigen-specific Tregs, that is expected to restore immune tolerance in subjects with airway allergic diseases (AAD).

Methods

A bio-nanoparticle, designated Rexo, containing an antigen/MHC II complex and R848, was naturally assembled in dendritic cells, that was released as an exosome. An AAD mouse model was developed used to test the effects of Rexo on restoring the immune tolerance in the airways.

Results

Exposure to R848 failed to induce Tregs in the β6-deficient mouse airway tissues, that were successfully induced in wild type mice. The results were validated inin vitro experiments. R848 activated the TLR7/MyD88/p38 signal pathway to increase the αvβ6 levels in CD4⁺ T cells, the αvβ6 then converted the TGF-β precursor to its mature form, and thus, induced Treg generation. Administration of Rexo restored the antigen-specific immune tolerance in the airways manifesting efficiently suppressing experimental AAD by inducing antigen-specific Tregs in the airways and inhibiting antigen-specific Th2 response.

Conclusions

Rexos can inhibit experimental AAD via inducing antigen-specific Tregs to restore immune tolerance in the airway tissues, suggesting that Rexos have the translational potential to be used in the treatment of AAD.

中文翻译：

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整合素αvβ6与瑞喹莫特合作恢复气道过敏中的抗原特异性免疫耐受

背景

整合素 αvβ6 可以将转化生长因子 (TGF)-β 前体转化为成熟形式。Resiquimod (R848) 可以产生产生 TGF-β 的调节性 T 细胞 (Treg)。因此，同时施用特定抗原和 R848 可能会产生抗原特异性 Treg，这有望在患有气道过敏性疾病 (AAD) 的受试者中恢复免疫耐受。

方法

一种命名为 Rexo 的生物纳米颗粒，含有抗原/MHC II 复合物和 R848，在树突细胞中自然组装，并作为外泌体释放。开发了 AAD 小鼠模型，用于测试 Rexo 对恢复气道免疫耐受的影响。

结果

暴露于 R848 未能在 β6 缺陷的小鼠气道组织中诱导 Tregs，而在野生型小鼠中成功诱导。结果在体外实验中得到验证。R848 激活 TLR7/MyD88/p38 信号通路以增加 CD4 ⁺ T 细胞中的 αvβ6 水平，然后 αvβ6 将 TGF-β 前体转化为其成熟形式，从而诱导 Treg 生成。Rexo 的给药恢复了气道中的抗原特异性免疫耐受，通过诱导气道中的抗原特异性 Tregs 和抑制抗原特异性 Th2 反应来有效抑制实验性 AAD。

结论

Rexos 可以通过诱导抗原特异性 Tregs 来抑制实验性 AAD，以恢复气道组织的免疫耐受，表明 Rexos 具有用于治疗 AAD 的转化潜力。