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Title: | Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis. | Authors: | Dick J.;Nagai K.;O'Sullivan K.M.;Oudin V.;Shim R.;Holdsworth S.R. ;Ooi J.D.;Chan A. ;Gan P.-Y.;Kitching A.R. | Institution: | (Gan, Chan, Ooi, Dick, Nagai, O'Sullivan, Oudin, Shim, Kitching, Holdsworth) Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia (Gan, Holdsworth) Department of Nephrology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia (Nagai) Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan (Kitching, Holdsworth) Department of Immunology, Monash Health, Monash Medical Centre, Clayton, Victoria, Australia | Issue Date: | 17-Oct-2019 | Copyright year: | 2019 | Publisher: | Elsevier B.V. | Place of publication: | Netherlands | Publication information: | Kidney International. 96 (5) (pp 1121-1133), 2019. Date of Publication: November 2019. | Journal: | Kidney International | 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.Copyright © 2019 International Society of Nephrology | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1016/j.kint.2019.05.012 | PubMed URL: | 31443998 [http://www.ncbi.nlm.nih.gov/pubmed/?term=31443998] | ISSN: | 0085-2538 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/36008 | Type: | Article | Subjects: | neutrophil priority journal protein targeting *target cell *Th1 cell *Th17 cell *antibody immunoglobulin G/ec [Endogenous Compound] interleukin 12p35/ec [Endogenous Compound] interleukin 17/ec [Endogenous Compound] interleukin 23p19/ec [Endogenous Compound] interleukin 6/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] *monoclonal antibody/dt [Drug Therapy] *myeloperoxidase unclassified drug CCR6 gene Cxr3 gene ifng gene IL17A gene STAT4 gene tgfb1 gene *interleukin 12p 40 antibody/dt [Drug Therapy] *interleukin 12p35 antibody/dt [Drug Therapy] *interleukin 23p19 antibody/dt [Drug Therapy] *myeloperoxidase antibody nonhuman albuminuria animal cell animal experiment animal model antibody titer article *autoimmunity CD4+ T lymphocyte controlled study cytokine production cytokine response disease severity drug efficacy drug response gene gene expression *glomerulonephritis/dt [Drug Therapy] humoral immunity immune response leukocyte macrophage mouse drug efficacy drug response gene gene expression *glomerulonephritis / *drug therapy humoral immunity immune response leukocyte macrophage mouse neutrophil nonhuman priority journal protein targeting *target cell *Th1 cell *Th17 cell animal model animal cell albuminuria animal experiment antibody titer Article *autoimmunity CD4+ T lymphocyte controlled study cytokine production cytokine response disease severity |
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