title: 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.
abstract: BACKGROUND
  Naturally occurring CD4+CD25+ 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 CD4+CD25+ Treg cells has also been investigated.
  
  
  METHODS
  Female 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 CD4+CD25+FoxP3+ Treg peripheral blood leukocyte was detected with mouse regulatory T cell staining kit by flowcytometry. Purified CD4+CD25+ Tregs were assessed for immune suppressive activity using the mixed lymphocyte reaction.
  
  
  RESULTS
  The 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 CD4+CD25+Foxp3+ Treg cells in both groups of mice. In contrast, the suppressive capacity of CD4+CD25+ Treg cells in splenocytes was markedly augmented in Y27-treated mice ex vivo.
  
  
  CONCLUSIONS
  Experimental evidence of the protect effects of Y27 against autoimmune nephritis has been shown. The mechanism may involve enhancement of the suppressive capacity of CD4+CD25+ Treg cells.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Xiao
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Chen
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Cheng
authors.forename: Wen-Xia
authors.initials: WX
authors.lastname: Zhou
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.forename: Ri-Fang
authors.initials: RF
authors.lastname: Yang
authors.forename: Liu-Hong
authors.initials: LH
authors.lastname: Yun
mesh_terms: D000284:Administration, Oral; D019264:Adoptive Transfer / Q000009:adverse effects / Q000379:methods; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D005559:Formamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D006912:Hydroxyquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D015394:Molecular Structure; D011507:Proteinuria / Q000276:immunology / Q000517:prevention & control; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D051858:Forkhead Transcription Factors; D005559:Formamides; C498833:Foxp3 protein, mouse; D006912:Hydroxyquinolines; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; C031066:formamide