間葉系幹細胞由来製剤「Exo-d-MAPPS」の慢性気道炎症抑制効果の分子・細胞機構の解明

Molecular and Cellular Mechanisms Responsible for Beneficial Effects of Mesenchymal Stem Cell-Derived Product "Exo-d-MAPPS" in Attenuation of Chronic Airway Inflammation.

• Carl Randall Harrell
• Dragica Miloradovic
• Ruxana Sadikot
• Crissy Fellabaum
• Bojana Simovic Markovic
• Dragana Miloradovic
• Aleksandar Acovic
• Valentin Djonov
• Nebojsa Arsenijevic
• Vladislav Volarevic

抄録

間葉系幹細胞（MSC）は、肺胞上皮細胞への分化能や免疫抑制作用を有することから、慢性閉塞性肺疾患（COPD）をはじめとする炎症性肺疾患の細胞治療における新たな治療薬として期待されている。本研究では、新たに設計された MSC 由来製品「Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)」の慢性気道炎症抑制効果を、COPD の動物モデル（慢性的なタバコの煙（CS）曝露により誘発される）と Exo-d-MAPPS を投与した COPD 患者の臨床データを用いて検討しました。Exo-d-MAPPSは、可溶性TNF受容体IおよびII、IL-1受容体アンタゴニスト、可溶性高度糖化最終産物受容体など、慢性気道炎症を抑制する免疫調節因子を高濃度に含有していることから、Exo-d-MAPPSは、慢性気道炎症を抑制する免疫調節因子として注目されています。その結果、Exo-d-MAPPSは呼吸機能を有意に改善し、炎症性サイトカイン（TNF-、IL-1、IL-12、IFN-）の血清中濃度を低下させ、免疫抑制作用のあるIL-10の血清中濃度を上昇させ、CS暴露マウスの慢性気道炎症を減衰させた。肺の細胞メイクアップから、Exo-d-MAPPS治療は、肺に浸潤したマクロファージ、好中球、ナチュラルキラーおよびナチュラルキラーT細胞における炎症性サイトカインの産生を減衰させ、肺に浸潤したマクロファージおよび樹状細胞（DC）の抗原提示特性を緩和させることが明らかになった。さらに、Exo-d-MAPPSは、炎症を起こした肺の免疫抑制性IL-10産生交代活性化マクロファージ、調節性DC、およびCD4+FoxP3+T調節性細胞の拡大を促進し、慢性気道炎症の減衰をもたらした。同様に、動物モデルで観察されたように、Exo-d-MAPPSはCOPD患者の肺の状態とQOLを有意に改善しました。重要なことに、Exo-d-MAPPSは忍容性に優れており、30名のCOPD患者のうち、Exo-d-MAPPS投与後に副作用を報告した患者はいませんでした。以上のことから、Exo-d-MAPPSは、慢性炎症性肺疾患の治療における新たな治療薬となりうる可能性があり、大規模臨床試験でその有効性がさらに検討されるべきであると考えています。

Mesenchymal stem cells (MSCs), due to their potential for differentiation into alveolar epithelial cells and their immunosuppressive characteristics, are considered a new therapeutic agent in cell-based therapy of inflammatory lung disorders, including chronic obstructive pulmonary disease (COPD). Since most of the MSC-mediated beneficent effects were the consequence of their paracrine action, herewith, we investigated the effects of a newly designed MSC-derived product "Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)" in the attenuation of chronic airway inflammation by using an animal model of COPD (induced by chronic exposure to cigarette smoke (CS)) and clinical data obtained from Exo-d-MAPPS-treated COPD patients. Exo-d-MAPPS contains a high concentration of immunomodulatory factors which are capable of attenuating chronic airway inflammation, including soluble TNF receptors I and II, IL-1 receptor antagonist, and soluble receptor for advanced glycation end products. Accordingly, Exo-d-MAPPS significantly improved respiratory function, downregulated serum levels of inflammatory cytokines (TNF-, IL-1, IL-12, and IFN-), increased serum concentration of immunosuppressive IL-10, and attenuated chronic airway inflammation in CS-exposed mice. The cellular makeup of the lungs revealed that Exo-d-MAPPS treatment attenuated the production of inflammatory cytokines in lung-infiltrated macrophages, neutrophils, and natural killer and natural killer T cells and alleviated the antigen-presenting properties of lung-infiltrated macrophages and dendritic cells (DCs). Additionally, Exo-d-MAPPS promoted the expansion of immunosuppressive IL-10-producing alternatively activated macrophages, regulatory DCs, and CD4+FoxP3+T regulatory cells in inflamed lungs which resulted in the attenuation of chronic airway inflammation. In a similar manner, as it was observed in an animal model, Exo-d-MAPPS treatment significantly improved the pulmonary status and quality of life of COPD patients. Importantly, Exo-d-MAPPS was well tolerated since none of the 30 COPD patients reported any adverse effects after Exo-d-MAPPS administration. In summing up, we believe that Exo-d-MAPPS could be considered a potentially new therapeutic agent in the treatment of chronic inflammatory lung diseases whose efficacy should be further explored in large clinical trials.

Copyright © 2020 Carl Randall Harrell et al.