A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells

Guilin Qiao; Lifen Yang; Zhenping Li; James W Williams; Jian Zhang

doi:10.1016/j.clim.2015.01.006

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A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells

Journal article

Peer reviewed

A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells

Guilin Qiao, Lifen Yang, Zhenping Li, James W Williams and Jian Zhang

Clinical immunology (Orlando, Fla.), Vol.157(2), pp.166-174

04/2015

DOI: 10.1016/j.clim.2015.01.006

PMID: 25638413

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Abstract

Lupus nephritis (LN) is a challenging problem that affects 50% of patients with systemic lupus erythematosus (SLE) without effective therapy. Here, we report that A77 1726, the active metabolite of leflunomide, effectively inhibits development of LN and attenuates the generalized autoimmune features. A77 1726 suppresses the expansion of double negative (DN) T cells, and inhibits T and B cell activation. Intriguingly, A77 1726 treatment significantly increases CD4(+)Foxp3(+) regulatory T cells but suppresses potential "pathogenic" IL-17-producing DN T cells in lymph nodes. In vitro experiment shows that A77 1726 potentiates the conversion of naive CD4(+)CD25(-) T cells into CD4(+)CD25(+)Foxp3(+) inducible regulatory T cells (iTregs) by inhibiting Akt. Taken together, our data indicate that the therapeutic effects of A77 1726 in murine LN are mediated, at least in part, by augmenting iTregs which suppress pathogenic IL-17-producing DN T cells through an Akt-dependent mechanism.

Lupus Nephritis - pathology

T-Lymphocyte Subsets - immunology

Aniline Compounds - pharmacology

Kidney - drug effects

Kidney - pathology

Antibodies, Antinuclear - immunology

Interleukin-17 - secretion

Interleukin-17 - immunology

Kidney - immunology

Lupus Nephritis - immunology

T-Lymphocytes, Regulatory - immunology

T-Lymphocytes, Regulatory - drug effects

Animals

T-Lymphocyte Subsets - drug effects

Mice

Hydroxybutyrates - pharmacology

T-Lymphocyte Subsets - secretion

Proto-Oncogene Proteins c-akt - metabolism

Immunosuppressive Agents - pharmacology

Disease Models, Animal

Details

Title: Subtitle: A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells
Creators: Guilin Qiao - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA
Lifen Yang - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA
Zhenping Li - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA
James W Williams - Cinkate Pharmaceutical Corporation, Chicago, IL 60605, USA. Electronic address: jwilliams@cinkate.com
Jian Zhang - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA. Electronic address: Jian.zhang@osumc.edu
Resource Type: Journal article
Publication Details: Clinical immunology (Orlando, Fla.), Vol.157(2), pp.166-174
Publisher: United States
DOI: 10.1016/j.clim.2015.01.006
PMID: 25638413
ISSN: 1521-6616
eISSN: 1521-7035
Grant note: name: Cinkate Pharmaceutical Corporation
Language: English
Date published: 04/2015
Academic Unit: Pathology
Record Identifier: 9984047897502771

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