Apremilast Ameliorates Experimental Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of CD4+Foxp3+ Regulatory T Cells Differentiation

Frontiers in Immunology

卷:9

Zhenjian Xu¹  Feng Huang¹  Gregory S. Lewis²  Hwa bok Wee²  Wenbin Qian³  Rayford R. June⁴  Julie Wang⁴  Song Guo Zheng⁴  Weiqian Chen⁴  Jin Lin⁵  Jilin Ma⁶  Peter H. Schafer⁷ 

[1] Department of Clinical Immunology, Third Affiliated Hospital, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China;

[2] Department of Orthopaedics and Rehabilitation, Penn State University Hershey College of Medicine, Hershey, PA, United States;

[3] Division of Hematology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;

[4] Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA, United States;

[5] Division of Rheumatology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;

[6] Division of Rheumatology, Immunology, and Nephrology, Zhejiang Traditional Chinese Medicine and Western Medicine Hospital, Hangzhou, China;

[7] Translational Development, Inflammation and Immunology, Celgene Corporation, Summit, NJ, United States;

关键词: rheumatoid arthritis;    collagen CII-induced arthritis;    phosphodiesterase 4;    Apremilast;    regulatory T and Th17 cells;   

DOI  :  10.3389/fimmu.2018.01662

来源: DOAJ

【 摘 要 】

Apremilast is a novel phosphodiesterase 4 (PDE4) inhibitor suppressing immune and inflammatory responses. We assessed the anti-inflammatory effects of Apremilast in type II collagen (CII)-induced arthritis (CIA) mouse model. To determine whether Apremilast can ameliorate arthritis onset in this model, Apremilast was given orally at day 14 after CII immunization. Bone erosion was measured by histological and micro-computed tomographic analysis. Anti-mouse CII antibody levels were measured by enzyme-linked immunosorbent assay, and Th17, Th1 cells, and CD4+Foxp3+ regulatory T (Treg) cells were assessed by flow cytometry in the lymph nodes. Human cartilage and rheumatoid arthritis (RA) synovial fibroblasts (RASFs) implantation in the severe combined immunodeficiency mouse model of RA were used to study the role of Apremilast in the suppression of RASF-mediated cartilage destruction in vivo. Compared with untreated and vehicle control groups, we found that Apremilast therapy delayed arthritis onset and reduced arthritis scores in the CIA model. Total serum IgG, IgG1, IgG2a, and IgG2b were all decreased in the Apremilast treatment groups. Moreover, Apremilast markedly prevented the development of bone erosions in CIA mice by CT analysis. Furthermore, in the Apremilast treated group, the frequency of Th17 cells and Th1 cells was significantly decreased while Treg cells’ frequency was significantly increased. The high dose of Apremilast (25 mg/kg) was superior to low dose (5 mg/kg) in treating CIA. Apremilast treatment reduced the migratory ability of RASFs and their destructive effect on cartilage. Compared with the model group, Apremilast treatment significantly reduced the RASFs invasion cartilage scores in both primary implant and contralateral implant models. Our data suggest that Apremilast is effective in treating autoimmune arthritis and preventing the bone erosion in the CIA model, implicating its therapeutic potential in patients with RA.

【 授权许可】

Unknown