Y27, a novel derivative of 4-hydroxyquinoline-3-formamide, prevents the development of murine systemic lupus erythematosus-like diseases in MRL-lpr autoimmune mice and BDF1 hybrid miceReport as inadecuate




Y27, a novel derivative of 4-hydroxyquinoline-3-formamide, prevents the development of murine systemic lupus erythematosus-like diseases in MRL-lpr autoimmune mice and BDF1 hybrid mice - Download this document for free, or read online. Document in PDF available to download.

Arthritis Research and Therapy

, 14:R235

First Online: 01 November 2012Received: 01 April 2012Revised: 15 September 2012Accepted: 29 October 2012

Abstract

IntroductionNaturally occurring CD4CD25 regulatory T Treg cells are central to the maintenance of peripheral tolerance. Impaired activity and-or a lower frequency of these cells lead to systemic lupus erythematosus SLE. Manipulating the number or activity of Treg cells is to be a promising strategy in treating it and other autoimmune diseases. We have examined the effects of Y27, a novel derivative of 4-hydroxyquinoline-3-formamide, on SLE-like symptoms in MRL-lpr autoimmune mice and BDF1 hybrid mice. Whether the beneficial effect of Y27 involves modulation of CD4CD25 Treg cells has also been investigated.

MethodsFemale MRL-lpr mice that spontaneously develop lupus were treated orally by gavage with Y27 for 10 weeks, starting at 10 weeks of age. BDF1 mice developed a chronic graft-versus-host disease GVHD by two weekly intravenous injections of parental female DBA-2 splenic lymphocytes, characterized by immunocomplex-mediated glomerulonephritis resembling SLE. Y27 was administered to chronic GVHD mice for 12 weeks. Nephritic symptoms were monitored and the percentage of CD4CD25FoxP3 Treg peripheral blood leukocyte was detected with mouse regulatory T cell staining kit by flowcytometry. Purified CD4CD25 Tregs were assessed for immune suppressive activity using the mixed lymphocyte reaction.

ResultsThe life-span of MRL-lpr mice treated with Y27 for 10 weeks was significantly prolonged, proteinuria and renal lesion severity were ameliorated, and blood urea nitrogen, triglyceride and serum anti-double-stranded DNA antibodies were decreased. Similar results were found in chronic GVHD mice. Administration of Y27 had little impact on percentage of the peripheral blood lymphocyte CD4CD25Foxp3 Treg cells in both groups of mice. In contrast, the suppressive capacity of CD4CD25 Treg cells in splenocytes was markedly augmented in Y27-treated mice ex vivo.

ConclusionsExperimental evidence of the protect effects of Y27 against autoimmune nephritis has been shown. The mechanism may involve enhancement of the suppressive capacity of CD4CD25 Treg cells.

AbbreviationsANOVAanalysis of variance

anti-dsDNAanti-double-stranded DNA

APCallophycocyanin

BUNblood urea nitrogen

CYCcyclophosphamide

ELISAenzyme-linked immunosorbent assay

FACSfluorescence activated cell sorter

FBSfetal bovine serum

FITCfluorescein isothiocyanate

FoxP3forkhead box P3

GVHDgraft-versus-host disease

HRPhorseradish peroxidase

IFN-γinterferon-γ

IgGimmunoglobulin G

ILinterleukin

ivintravenous

MACSmagnetic-activated cell sorting

MLRmixed lymphocyte reaction

MSmultiple sclerosis

PEphycoerythrin

SEMstandard error of the mean

SLEsystemic lupus erythematosus

Tconvconventional CD4CD25 effector T cells

TGF-βtransforming growth factor β

TMB3, 3-, 5, 5-tetramethylbenzidine

TNF-αtumor necrosis factor-α

Tregregulatory T.

Electronic supplementary materialThe online version of this article doi:10.1186-ar4078 contains supplementary material, which is available to authorized users.

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Author: Zhi-Yong Xiao - Shao-Hui Chen - Jun-Ping Cheng - Wen-Xia Zhou - Yong-Xiang Zhang - Ri-Fang Yang - Liu-Hong Yun

Source: https://link.springer.com/







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