Format

Send to

Choose Destination
Kidney Int. 2019 Nov;96(5):1121-1133. doi: 10.1016/j.kint.2019.05.012. Epub 2019 May 27.

Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis.

Author information

1
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia. Electronic address: Poh-yi.gan@monash.edu.
2
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.
3
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia; Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan.
4
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia; Department of Immunology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia.
5
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia; Department of Immunology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia.

Abstract

Anti-myeloperoxidase nephritogenic autoimmunity induces severe glomerulonephritis. To assess the therapeutic potential of monoclonal antibodies targeting T helper (Th) subset differentiation determining cytokines, we studied a murine model of anti-myeloperoxidase glomerulonephritis. The temporal participation of T helper subsets was determined by quantitating gene expression of CD4+ T-cells isolated from nephritic kidneys and cytokine production by lymphocytes from nodes draining myeloperoxidase immunization sites. Th17 cytokines (IL-17A and IL-6) rose rapidly but declined as autoimmunity matured when Th1 cytokines (IL-12 and TNF) predominated. Therefore, T helper subset participation in anti-myeloperoxidase autoimmunity is biphasic, with Th17 early and Th1 late. To confirm the functional relevance of this biphasic pattern, we compared systemic anti-myeloperoxidase autoimmunity in wild type, Th17 deficient and Th1 deficient mice. Early, Th1 deficient mice developed similar autoimmunity and glomerulonephritis to wild type mice. However, Th17 deficient mice had significantly reduced anti-myeloperoxidase autoimmunity. In late autoimmunity, Th1 deficient mice developed reduced autoimmunity and were protected from anti-myeloperoxidase glomerulonephritis. The therapeutic potential of these findings were demonstrated by neutralizing monoclonal antibodies. Targeting IL-23p19 attenuated early Th17 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not late phase disease. Targeting IL-12p35 attenuated late phase Th1 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not early autoimmunity or glomerulonephritis. Targeting both T helper subsets with an anti-IL-12p40 monoclonal antibody was effective during both early and late phases of anti-myeloperoxidase glomerulonephritis. Thus, definition of dominant T helper differentiating subsets in anti-myeloperoxidase glomerulonephritis by renal CD4+ T-cell cytokine gene expression allows effective proper phase monoclonal antibody treatment of anti-myeloperoxidase glomerulonephritis.

KEYWORDS:

ANCA; autoimmune disease; biologicals; chronic kidney disease; focal segmental glomerulonephritis; glomerulonephritis; myeloperoxidase

PMID:
31443998
DOI:
10.1016/j.kint.2019.05.012

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center