chiniofon and Glomerulonephritis

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.. 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.. 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.. 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.

Topics: Administration, Oral; Adoptive Transfer; Animals; Autoantibodies; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Forkhead Transcription Factors; Formamides; Glomerulonephritis; Graft vs Host Disease; Hydroxyquinolines; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Kidney; Lupus Erythematosus, Systemic; Mice, Inbred CBA; Mice, Inbred DBA; Mice, Inbred MRL lpr; Molecular Structure; Proteinuria; T-Lymphocytes, Regulatory; Transforming Growth Factor beta1

Autoimmune MRL/1 mice were treated with a recently developed substance with immunomodulating properties, LS-2616. Treatment was initiated at the age of 8 weeks, before the onset of clinically apparent disease, and at 16 weeks of age, after development of established lupus disease. Beneficial therapeutic effects were obtained, even when LS-2616 was administered at the lowest dose tested (1 mg/mouse/week) to 16-week-old mice. The effects of LS-2616 on longevity, as well as on development of lymphadenopathy, splenomegaly, glomerulonephritis, and vasculitis, were pronounced and were comparable with those of cyclophosphamide. The results obtained suggest a potential role for LS-2616 in the treatment of autoimmune disease in humans.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Cyclophosphamide; Drug Evaluation, Preclinical; Female; Glomerulonephritis; Hydroxyquinolines; Immunity; Lymphatic Diseases; Mice; Mice, Inbred Strains; Splenomegaly; Vasculitis