Neutralizing the IL-7Rα limits injury in experimental ANCA-associated glomerulonephritis

被引:0
作者
Alikhan, Maliha A. [1 ]
Kishimoto, Kazuya [1 ]
Wong, Limy [1 ,2 ,3 ]
Prakongtham, Peemapat [1 ]
Auden, Alana [1 ]
O'Sullivan, Kim M. [1 ]
Jaw, Juli [1 ,4 ]
Kitching, A. Richard [1 ,4 ,5 ]
机构
[1] Monash Univ, Ctr Inflammatory Dis, Monash Med Ctr, Dept Med, Clayton, Vic, Australia
[2] Monash Univ, Dept Med, Eastern Hlth Clin Sch, Box Hill, Vic, Australia
[3] Eastern Hlth, Dept Renal Med, Box Hill, Vic, Australia
[4] Monash Hlth, Dept Nephrol, Clayton, Vic, Australia
[5] Monash Hlth, Dept Paediat Nephrol, Clayton, Vic, Australia
基金
英国医学研究理事会;
关键词
ANCA; glomerulonephritis; IL-7R alpha; T lymphocytes; vasculitis; ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES; T-CELL EXHAUSTION; MYELOPEROXIDASE; INTERLEUKIN-7; BLOCKADE; IL-7; GRANULOMATOSIS; STIMULATION; RECOMBINANT; SIGNATURE;
D O I
10.1093/ndt/gfae276
中图分类号
R3 [基础医学]; R4 [临床医学];
学科分类号
1001 ; 1002 ; 100602 ;
摘要
Background and hypothesis Increased T-cell interkeukin (IL)-7R alpha signalling is associated with a poorer prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. These studies examined the functional role of IL-7R alpha (CD127) in experimental glomerulonephritis mediated by anti-myeloperoxidase (MPO) T-cell autoimmunity. We hypothesized that T cells would express IL-7R alpha in the kidney and that blocking the function of IL-7R alpha, without cellular depletion, would be protective.Methods Mice were immunized with mouse MPO, then low-dose sheep anti-mouse basement membrane globulin was administered to trigger glomerulonephritis. Flow cytometry and RNA-sequencing characterized intrarenal CD127+-expressing CD4+ and CD8+ T cells in mice with anti-MPO glomerulonephritis. To assess the functional role of IL-7R alpha, mice with established anti-MPO autoimmunity were treated with anti-IL-7R alpha antibodies.Results Control ovalbumin-immunized mice given anti-basement membrane globulin developed minimal injury, while MPO-immunized mice given anti-basement membrane globulin developed albuminuria with glomerular and tubulointerstitial injury. Numbers of intrarenal IL-7R alpha+ (CD127+) CD4+ and CD8+ T cells were increased in mice with anti-MPO glomerulonephritis. There were 3738 and 2726 genes differentially expressed between intrarenal CD127-PD-1+ and CD127+PD-1- CD8+ and CD4+ T cells, respectively, with substantially overlapping differentially expressed genes between CD8+ and CD4+ T cells. Both CD127-PD-1+ CD8+ and CD4+ T cells were enriched for previously described T-cell exhaustion signatures associated with prognosis in autoimmune disease. As effector memory T cells drive inflammation, we blocked the IL-7R alpha after inducing anti-MPO autoimmunity. Anti-IL-7R alpha antibodies limited histological injury, and reduced albuminuria numbers of glomerular and interstitial leucocytes, with reduced intrarenal chemokine and pro-inflammatory cytokine expression.Conclusions Intrarenal effector memory and exhausted CD4+ and CD8+ T cells are present in experimental anti-MPO glomerulonephritis. Neutralizing effector T cells via the IL-7R alpha after the induction of autoimmunity limits intrarenal inflammation and disease. IL-7R alpha may be a therapeutic target in ANCA-associated vasculitis.
引用
收藏
页码:1350 / 1361
页数:12
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