@article{12bf2897835242c8953cc351884f3c12,
title = "Tocilizumab monotherapy uncovered the role of the CCL22/17-CCR4+ Treg axis during remission of crescentic glomerulonephritis",
abstract = "Objectives: Tocilizumab (TCZ) is a humanised anti-interleukin (IL)-6 receptor (IL-6R) monoclonal antibody that is a promising agent to treat various autoimmune diseases. However, the mechanism of TCZ efficacy is unclear. This study aims to elucidate the relationship between Tregs and IL-6R blockade in autoimmunity-mediated renal disease based on a TCZ-treated cohort of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and in an experimental model of crescentic glomerulonephritis (cGN). Methods: We examined multiple serum levels of cytokines and chemokines and peripheral blood mononuclear cells in patients with AAV who received TCZ monotherapy and achieved drug-free remission. Moreover, we investigated the mechanistic role of IL-6R blockade in accelerated cGN model to analyse the local sites of inflammation. Results: Serum chemokines CCL22 and CCL17, in addition to the CCR4+Foxp3+ Treg population, increased in patients who demonstrated drug-free remission after the cessation of TCZ. In the cGN model, IL-6R blockade ameliorated the disease, elevated CCL22/17 in CD206+CD11b+CD11c+ kidney M2-like type macrophages, and increased the migration of Tregs into the kidney and regional lymph nodes. The local administration of CCL22 in the kidney facilitated Treg accumulation and reduced glomerular crescent formation. Conclusions: This study revealed a new mechanism whereby effector Tregs migrate into the inflammatory kidney via the CCL22/17–CCR4 axis that is facilitated by M2-like type macrophages that are induced by IL-6R blockade.",
keywords = "ANCA-associated vasculitis, CCL22/17–CCR4 axis, IL-6, M2-like type macrophages, Tregs, crescentic glomerulonephritis, tocilizumab",
author = "Ryota Sakai and Minako Ito and Keiko Yoshimoto and Shunsuke Chikuma and Takahiko Kurasawa and Tsuneo Kondo and Katsuya Suzuki and Tsutomu Takeuchi and Koichi Amano and Akihiko Yoshimura",
note = "Funding Information: MR16‐1 was provided by Chugai Pharmaceutical Co., Ltd. We thank Y Hirata, Y Tokifuji, and Y Noguchi for technical assistance. RS was supported by a {\textquoteleft}Kibou Projects{\textquoteright} Scholarship for Doctoral Students in Immunology (funded by Tadamitsu Kishimoto and the Japanese Society for Immunology). We thank all clinical research assistants in the Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, including T Kukita, I Ohshima, M Sato, Ma Suzuki, Mi Suzuki, M Kawamura and M Sawada. We thank all clinical research and technical assistants in the Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, including Y Ikeda and Y Taguchi. We thank Enago ( www.enago.jp ) for the English language review. Funding Information: This study was supported by JSPS KAKENHI (S) JP17H06175, Challenging Research (P) JP18H05376, and AMED‐CREST JP19gm1110009 to AY and Keio University Doctorate Student Grant‐in‐Aid Program to RS. This study was also supported by the Takeda Science Foundation, the Uehara Memorial Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Bristol‐Myers Squibb Research grant, the Kanae Foundation, and the SENSHIN Medical Research Foundation. Funding Information: MR16-1 was provided by Chugai Pharmaceutical Co., Ltd. We thank Y Hirata, Y Tokifuji, and Y Noguchi for technical assistance. RS was supported by a ?Kibou Projects? Scholarship for Doctoral Students in Immunology (funded by Tadamitsu Kishimoto and the Japanese Society for Immunology). We thank all clinical research assistants in the Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, including T Kukita, I Ohshima, M Sato, Ma Suzuki, Mi Suzuki, M Kawamura and M Sawada. We thank all clinical research and technical assistants in the Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, including Y Ikeda and Y Taguchi. We thank Enago (www.enago.jp) for the English language review. Publisher Copyright: {\textcopyright} 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.",
year = "2020",
doi = "10.1002/cti2.1203",
language = "English",
volume = "9",
journal = "Clinical and Translational Immunology",
issn = "2050-0068",
publisher = "Nature Publishing Group",
number = "11",
}