Department of Respiratory Medicine, Kawasaki Medical School, Okayama, Japan.
Torii Pharmaceutical Co., Ltd., Tokyo, Japan.
Clin Exp Immunol. 2022 Jun 11;208(2):202-211. doi: 10.1093/cei/uxac024.
Allergen-specific sublingual immunotherapy (SLIT) is a potentially effective disease-modification treatment for patients with allergic asthma. Because CD44 signaling enhances regulatory T (Treg) cell-induction, administering CD44 ligands such as hyaluronan (HA) with allergen-specific SLIT may enhance the therapeutic effects. We evaluated the role of CD44 in Treg cell-induction in T helper type 2 (Th2)-mediated chronic airway inflammation using CD44-/- mice and the efficacy of HA on SLIT in a Dermatophagoides farinae (Df)-induced murine model of chronic asthma. Th2 responses and Treg cell induction were evaluated in CD44-/- mice. We devised a new SLIT model of Df-induced chronic asthma utilizing HA as an adjuvant. The effects of HA added to the new SLIT model were evaluated by the early asthmatic response (EAR) and airway hyperresponsiveness (AHR), eosinophilic airway inflammation, and serum Df-specific IgE levels. Th2-mediated chronic eosinophilic airway inflammation was worse in CD44-/- mice compared with Df-sensitized wild-type (WT) mice. HA enhanced the effect of Df-induced Treg cells in a CD44-dependent manner. Sublingual Df treatment in combination with HA, but not alone, normalized EAR and AHR, and significantly reduced the serum IgE levels and the bronchoalveolar lavage fluid (BALF) eosinophil number. HA also induced Treg cells in a Df-sensitized spleen cell culture in a CD44-dependent manner. The treatment-enhancing effects of HA in this SLIT model were diminished in CD44-/- mice. CD44 is a key contributor to Treg cell induction and critical for the enhancing effects of HA in a Df-induced murine model of chronic asthma.
变应原特异性舌下免疫疗法（SLIT）是一种潜在有效的疾病修饰治疗方法，可用于治疗过敏性哮喘患者。由于 CD44 信号增强调节性 T（Treg）细胞诱导，用变应原特异性 SLIT 给予 CD44 配体（如透明质酸（HA））可能会增强治疗效果。我们使用 CD44-/- 小鼠评估了 CD44 在 Th2 介导的慢性气道炎症中的 Treg 细胞诱导中的作用，以及 HA 在屋尘螨（Df）诱导的慢性哮喘小鼠模型中的 SLIT 中的疗效。在 CD44-/- 小鼠中评估了 Th2 反应和 Treg 细胞诱导。我们设计了一种利用 HA 作为佐剂的新型 Df 诱导的慢性哮喘 SLIT 模型。通过早期哮喘反应（EAR）和气道高反应性（AHR）、嗜酸性气道炎症和血清 Df 特异性 IgE 水平评估了 HA 添加到新型 SLIT 模型中的效果。与 Df 致敏的野生型（WT）小鼠相比，CD44-/- 小鼠中的 Th2 介导的慢性嗜酸性气道炎症更严重。HA 以 CD44 依赖的方式增强了 Df 诱导的 Treg 细胞的作用。与单独使用 Df 相比，联合使用 Df 和 HA 不仅可使 EAR 和 AHR 正常化，还可显著降低血清 IgE 水平和支气管肺泡灌洗液（BALF）嗜酸性粒细胞数量。HA 还以 CD44 依赖的方式在 Df 致敏的脾细胞培养物中诱导 Treg 细胞。在 CD44-/- 小鼠中，HA 在这种 SLIT 模型中的增强作用会降低。CD44 是 Treg 细胞诱导的关键贡献者，对于 HA 在 Df 诱导的慢性哮喘小鼠模型中的增强作用至关重要。
