Allergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan.
Allergol Int. 2014 May;63 Suppl 1:29-35. doi: 10.2332/allergolint.13-OA-0635.
The eosinophil is deeply associated with the pathogenesis of bronchial asthma and other allergic diseases. We recently identified a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10 (Mfsd10). A monoclonal antibody (mAb) against Mfsd10 (M2) showed selective binding and neutralizing activities for eosinophils. However, the relative potency of the blockage of Mfsd10 and other eosinophil-specific molecules for the treatment of allergic diseases has not been evaluated. Therefore, in this study, the effects of M2 and an anti-Siglec-F mAb on antigen-immunized and antigen-specific Th2 cell-transferred murine eosinophilic inflammation models were comparatively investigated.
Ovalbumin (OVA)-specific Th2 cells were differentiated from naïve CD4+ T cells of DO11.10/RAG-2-/- mice in vitro and cytokine producing activity of the Th2 cells was examined. OVA-immunized and Th2 cell-transferred BALB/c mice were treated with M2 or anti-Siglec-F and challenged with OVA. Then the number of inflammatory cells and the concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) were determined.
Antigen-specific Th2 cells produced large amounts of IL-4, IL-5 and IL-13 but not IL-17A or IFN-γ. Administration of M2 significantly suppressed antigen-induced lung eosinophil infiltration both in OVA-immunized and Th2 cell-transferred mice. The potency as well as selectivity of M2 for down-regulating eosinophils was quite similar to that of anti-Siglec-F. Both mAbs did not affect antigen-induced IL-5 production in the lungs.
Mfsd10 as well as Siglec-F could be an effective target to treat eosinophil-related disorders including bronchial asthma.
嗜酸性粒细胞与支气管哮喘和其他过敏性疾病的发病机制密切相关。我们最近鉴定了一种新型的嗜酸性粒细胞特异性细胞表面分子，主要易化剂超家族结构域包含 10 （Mfsd10）。针对 Mfsd10 的单克隆抗体（mAb）（M2）对嗜酸性粒细胞表现出选择性结合和中和活性。然而，尚未评估针对 Mfsd10 和其他嗜酸性粒细胞特异性分子的阻断相对效力，用于治疗过敏性疾病。因此，在这项研究中，比较研究了 M2 和抗 Siglec-F mAb 对抗原免疫和抗原特异性 Th2 细胞转移的小鼠嗜酸性粒细胞炎症模型的影响。
从 DO11.10/RAG-2-/- 小鼠的幼稚 CD4+ T 细胞体外分化卵清蛋白（OVA）特异性 Th2 细胞，并检查 Th2 细胞的细胞因子产生活性。用 M2 或抗 Siglec-F 处理 OVA 免疫和 Th2 细胞转移的 BALB/c 小鼠，并与 OVA 一起进行攻毒。然后测定支气管肺泡灌洗液（BALF）中的炎症细胞数量和 IL-5 浓度。
抗原特异性 Th2 细胞产生大量的 IL-4、IL-5 和 IL-13，但不产生 IL-17A 或 IFN-γ。M2 的给药显著抑制了 OVA 免疫和 Th2 细胞转移的小鼠中抗原诱导的肺嗜酸性粒细胞浸润。M2 下调嗜酸性粒细胞的效力和选择性与抗 Siglec-F 相当。两种 mAb 均不影响抗原诱导的肺部 IL-5 产生。
Mfsd10 以及 Siglec-F 可能是治疗包括支气管哮喘在内的嗜酸性粒细胞相关疾病的有效靶点。
