Suppressive effects of a quinoxaline-analogue (Rob 803) on pathogenic immune mechanisms in collagen-induced arthritis.
The anti-arthritic effects of the synthetic compound 9-chloro-2,3 dimethyl-6-(N,N-dimetylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rob 803) was evaluated by treating Dark Agouti rats with collagen-induced arthritis using three different protocols. Daily subcutaneous treatment with 40 mg/kg/day of Rob 803 from the day of immunization and 14 days forward suppressed arthritis severity significantly and delayed the onset of clinical arthritis. In contrast, similar treatment initiated when individual rats had developed clinical disease (at a score of 2 points) did not suppress disease. Oral treatment with 35 mg/kg/day of Rob 803 from the day of immunization and 21 days forward resulted in a trend towards disease suppression. In vitro analysis of rats treated subcutaneously with Rob 803 revealed an inhibition of T cell proliferation but no effect on the generation of an anti-CII immunoglobulin G response. Further in vitro analysis demonstrated that Rob 803 also inhibited the generation of nitric oxide in macrophages, although at higher concentrations than needed for inhibitory effects on T cell proliferation. Thus we report that early subcutaneous administration of the synthetic substance Rob 803 has anti-rheumatic effects that are probably mediated by affecting the proliferative capacity of lymph node T cells. Rob 803 should be considered as a new candidate substance for anti-rheumatic treatment.
Westman
E
E
Rheumatology Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden.
Thi Ngoc
D D
DD
Klareskog
L
L
Harris
H Erlandsson
HE
D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
C528674:9-chloro-2,3-dimethyl-6-(N,N-dimetylamino-2-oxoethyl)-6H-indolo(2,3-b)quinoxaline; D018501:Antirheumatic Agents; D024043:Collagen Type II; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011810:Quinoxalines; D009585:Nitrogen Dioxide