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.

Identification of biomarkers and pathways for focal segmental glomerulosclerosis using next generation sequencing data and bioinformatics analysis

“…Musante et al [437], Han et al [438], Zhang et al [439], Sato et al [440], Yang et al [441], El-Aouni et al [442], Perisic et al [443], Chung et al [444], Wilkening et al [445], Kahvecioglu et al [446], Hu et al [447] and Worthmann et al [448] revealed that ALB (albumin), KLF15, ATF3, LPL (lipoprotein lipase), CUBN (cubilin), ILK (integrin linked kinase), PLEKHH2, TNF (tumor necrosis factor), CCR2, SPON2, LRRC55 and IGFBP1 might be the potential targets for FSGS diagnosis and treatment. Alves et al [449], Ma et al [450], Esposito et al [451], Ai et al [452], Lu et al [453], Bui et al [454], Bao et al [455], Zuo et al [456], Su et al [457], Wang et al [458], Šalamon et al [459], Harskamp et al [460], Ćwiklińska et al [461], Hishida et al [462], Gunay-Aygun et al [463], Simpson et al [464], Svenningsen et al [465], Wang et al [466], Rao et al [467], Chen et al [468], Bedin et al [469], Cao et al [470], Jang et al [471], de Frutos et al [472], Lin et al [473], Wang et al [474], Liu and Zhuang [475], Feng et al [476], Yu et al [477], Reed et al [478], Milillo et al [479], Chen et al [74], Chen et al [480], Vieira et al [76], Charlton et al [481], Shi et al [482], Zhou et al [483], Nazari et al [241], Greene et al [484], Lazar et al [485], Jobst-Schwan et al [486], Du et al [487], Liu et al [85], Liu et al [488], Liu et al [489], Lee et al [490], Wen et al [491], Sakai et al [492], Zhang et al [493], Wang et al [494], CD5L Castelblanco et al [251], Chen et al [495], Swanson et al [496], Ksiazek, [497], Li et al [498], Zhang et a...…”

Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis

“…CD8α+ DCs are recognized to be distinct and most efficient in their capability for cross presentation, unique from non-CD8+ DCs [ 20 ] permitting antigen presentation for induction of tolerance [ 21 ]. IL-6 blockade leading to increased Treg and immune tolerance [ 22 ] or through M2 macrophages have been described [ 23 ]. We demonstrate here a novel aspect of peripheral tolerance through CD8α+IL10+ cDCs triggered by tocilizumab.…”

Regulatory T Cells in Autoimmune Vasculitis

“…Correlative studies associating improvement of CCR4 + FOXP3 + Treg cell frequencies with drug-free remission have supported the concept that ultimately, Treg cell frequencies are sensitive markers of the inflammatory status ( 152 ). In a mouse model, blocking IL-6 activity ameliorated the disease and increased the migration of Tregs into the kidney and the regional lymph nodes ( 152 ). In both GPA and MPA, B cell depletion therapy and conventional immunosuppressants yielded similar CD4 + Treg cell numbers ( 153 ).…”

“…Inhibition of tryptophan degradation enhances immune responsiveness, with a tendency to more severe glomerulonephritis (151). Correlative studies associating improvement of CCR4 + FOXP3 + Treg cell frequencies with drugfree remission have supported the concept that ultimately, Treg cell frequencies are sensitive markers of the inflammatory status (152). In a mouse model, blocking IL-6 activity ameliorated the disease and increased the migration of Tregs into the kidney and the regional lymph nodes (152).…”