TY - JOUR
T1 - Atializumab, a humanized anti-aminoacyl-tRNA synthetase-interacting multifunctional protein-1 (AIMP1) antibody significantly improves nephritis in (NZB/NZW) F1 mice
AU - Mun, Chin Hee
AU - Kim, Jin Ock
AU - Ahn, Sung Soo
AU - Yoon, Taejun
AU - Kim, Su Jeong
AU - Ko, Eunhee
AU - Noh, Hee Dong
AU - Park, Yong Beom
AU - Jung, Hak Jun
AU - Kim, Tae Sung
AU - Lee, Sang Won
AU - Park, Sang Gyu
N1 - Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education ( 2017R1D1A1B03029050 ) and a faculty research grant of Yonsei University College of Medicine ( 6-2016-0159 ). Also, this study was conducted by a research project with the support of Handok ( HANDOK-2017-005 ). In addition, this research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) ( NRF-2017R1A2B4002968 ).
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/11
Y1 - 2019/11
N2 - 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.
AB - 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.
KW - Aminoacyl-tRNA synthetase (ARS)-interacting multifunctional protein 1
KW - Atializumab
KW - Humanized antibody
KW - Inflammatory cytokine
KW - Lupus nephritis
KW - Lupus-prone mice
UR - http://www.scopus.com/inward/record.url?scp=85070076960&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2019.119408
DO - 10.1016/j.biomaterials.2019.119408
M3 - Article
C2 - 31394431
AN - SCOPUS:85070076960
SN - 0142-9612
VL - 220
JO - Biomaterials
JF - Biomaterials
M1 - 119408
ER -