title: 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.
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.
authors: Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
authors: Guilin
authors: G
authors: Qiao
authors: Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
authors: Lifen
authors: L
authors: Yang
authors: Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
authors: Zhenping
authors: Z
authors: Li
authors: Cinkate Pharmaceutical Corporation, Chicago, IL 60605, USA. Electronic address: jwilliams@cinkate.com.
authors: James W
authors: JW
authors: Williams
authors: 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.
authors: Jian
authors: J
authors: Zhang
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D003437:Crotonates; D004195:Disease Models, Animal; D006885:Hydroxybutyrates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009570:Nitriles; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014052:Toluidines
chemical_list: D000814:Aniline Compounds; D000974:Antibodies, Antinuclear; D003437:Crotonates; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D051057:Proto-Oncogene Proteins c-akt
keywords: Double negative T cells; IL-17; Leflunomide; Lupus nephritis; Regulatory T cells; Systemic lupus erythematosus