Abstract
IntroductionNaturally 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.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 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.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 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.ConclusionsExperimental 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.
Highlights
Occurring CD4+CD25+ regulatory T (Treg) cells are central to the maintenance of peripheral tolerance
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
The suppressive capacity of CD4+CD25+ T regulatory (Treg) cells in splenocytes was markedly augmented in Y27-treated mice ex vivo
Summary
Occurring CD4+CD25+ regulatory T (Treg) cells are central to the maintenance of peripheral tolerance. Systemic lupus erythematosus (SLE) is a disorder of immune regulation characterized by the breakdown of tolerance to self-nuclear, cytoplasmic and cell surface molecules, and the production of autoantibodies to them. Antibody- and immune complex-mediated inflammation develop a systemic autoimmune disorder resembling human SLE, characterized by autoantibody production, immunocomplex deposition and proteinuria [3,4,5]. In both these models, an abnormal function of CD4+CD25+ regulatory T (Treg) cells may play a pivotal role. In lupus-prone MRL/lpr mice developing a strong lupus disease, a reduced capacity to suppress proliferation and especially, to inhibit interferong (IFN-g) secretion by syngeneic effector CD4+CD25T cells occurs in vitro [16]. Expanding Treg or enhancing Treg suppressive activity in vivo offers a promising strategy in lupus treatment
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