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  • [Biomaterials.] Atializumab, a humanized anti-aminoacyl-tRNA synthetase-interacting multifunctional protein-1 (AIMP1) antibody significantly improves nephritis in (NZB/NZW) F1 mice.Atializumab (AIMP1에 대한 인간화 항체) : 루푸스 유발 마우스에서 신염(nephritis)을 개선 시킴.

    연세대, 아주대 / 문친희, 김진옥, 이상원*, 박상규*

  • 출처
    Biomaterials.
  • 등재일
    2019 Nov
  • 저널이슈번호
    220:119408. doi: 10.1016/j.biomaterials.2019.119408. Epub 2019 Aug 2.
  • 내용

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    Abstract
    Aminoacyl-tRNA synthetase (ARS)-interacting multifunctional protein 1 (AIMP1) enhances the expression of proinflammatory cytokines. In our previous study, we have shown that serum AIMP1 in patients with SLE was significantly higher than that of healthy controls. To address whether neutralization of AIMP1 could ameliorate nephritis in lupus-prone mice, we generated atializumab, a humanized antibody against AIMP1 and investigated its therapeutic efficacy. ELISA showed that serum AIMP1 at 23 weeks old was significantly higher than that at 13 weeks old in lupus-prone mice. Therefore, lupus-prone mice were randomly assigned to 5 groups (vehicle, methylprednisolone and 0.5, 2, and 5 mg/kg atializumab). After treatment, disease severity was assessed using a variety of phenotypes, including proteinuria, histological damages, renal deposition of immune-complex. In addition, serum cytokines, anti-dsDNA and IgG subclasses were determined. T cell subsets were analyzed using a fluorescence-activated cell sorter. Atializumab significantly diminished proteinuria, improved glomerular and tubular damages and reduced the renal deposition of immune-complexes. Moreover, atializumab significantly decreased serum interferon (IFN)-γ, interleukin (IL)-17A, and IL-6, whereas it increased serum IL-10. Similarly, atializumab reduced the numbers of TH1, TH2 and TH17 cells in a dose-dependent manner, while atializumab enhanced the number of regulatory T (Treg) cells. Furthermore, atializumab decreased not only splenic plasma cells and serum anti-dsDNA but also pathogenic IgG subclasses for nephritis. It suppressed NF-κB activation by inhibiting IκBα degradation in a dose-dependent manner in vitro. Atializumab alleviated nephritis by inhibiting autoreactive T, B, and plasma cells and decreasing NF-κB-related proinflammatory cytokines in lupus-prone mice. These results suggest that treatment targeting AIMP1 could be a novel and highly immune-modulating therapeutic strategy in lupus nephritis.

     


    Author information

    Mun CH1, Kim JO2, Ahn SS1, Yoon T1, Kim SJ1, Ko E1, Noh HD2, Park YB3, Jung HJ4, Kim TS4, Lee SW5, Park SG6.
    1
    Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
    2
    College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Republic of Korea.
    3
    Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.
    4
    Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
    5
    Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: sangwonlee@yuhs.ac.
    6
    College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Republic of Korea. Electronic address: sgpark@ajou.ac.kr.

  • 키워드
    Aminoacyl-tRNA synthetase (ARS)-interacting multifunctional protein 1; Atializumab; Humanized antibody; Inflammatory cytokine; Lupus nephritis; Lupus-prone mice
  • 편집위원

    AIMP1(Aminoacyl-tRNA synthetase-interacting multifunctional protein 1)은 염증반응을 촉진하는 proinflammatory cytokine이다. 이 논문은 AIMP1에 대한 인간화 항체인 atializumab의 개발 및 이 항체를 사용한 치료가 루푸스 유발 마우스의 신염(nephritis)을 완화 시킨다는 것을 보여주며, 루푸스 신염에 대한 새로운 면역치료법을 제시하고 있다.

    2020-01-03 15:59:36

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