The impact of a new immunomodulator oxo-quinoline-3-carboxamide on the progression of experimental lupus.
Autoimmune, lupus-prone MRL lpr/lpr mice were treated orally with oxo-quinoline-3-carboxamide (ABR-25757), a newly developed immunomodulator. Treatment was initiated in one set of experiment at the age of 10 weeks, before the onset of clinically apparent disease, and in another set at 15 weeks, after the development of established lupus disease. Beneficial therapeutic effects were obtained even when ABR-25757 was administered at the lowest dose tested (7.5 microg/mouse/week) to 15 weeks old mice with established lupus disease. The effects of ABR-25757 on longevity, as well as on development of glomerulonephritis were pronounced and comparable with those of LS-2616, a potent immunomodulator. Administration of ABR-25757 did not significantly alter T cell responses in vivo nor in vitro. In addition, it only marginally suppressed B cell responses measured as frequencies of immunoglobulin secreting cells. By the same token this compound did not affect overall leukocyte content in primary (bone marrow) or secondary (spleen) lymphoid tissues. In contrast, treatment with ABR-25757 up regulated expression of pro-inflammatory transcription factors NF-kappaB and AP-1. These results suggest (a) a potential therapeutic role of ABR-25757 in the treatment of experimental lupus and (b) that the effect of the treatment is mediated by immunodeviation rather than by immunosuppression.
Carlsten
Hans
H
Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Göteborg, Guldhedsgatan 10, S-413 46 Göteborg, Sweden. hans.carlsten@rheuma.gu.se
Jonsson
Charlotte
C
Bokarewa
Maria
M
Svensson
Lena
L
Tarkowski
Andrej
A
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D007136:Immunoglobulins / Q000276:immunology; D007155:Immunologic Factors / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D015363:Quinolones / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology
D007136:Immunoglobulins; D007155:Immunologic Factors; C497710:N-ethyl-N-phenyl-1,2-dihydro-5-ethyl-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide; D015363:Quinolones; D014157:Transcription Factors