Heterogeneous effects of IFN-gamma in adjuvant arthritis.
In an attempt to evaluate the role of IFN-gamma in autoimmune arthritis, we tested the effects of IFN-gamma and anti-IFN-gamma mAb (DB-1) in various phases of arthritis development in a rat model for rheumatoid arthritis; the adjuvant arthritis (AA) model, induced by immunization with CFA. In addition, the effects of IFN-gamma were tested in vitro on T cell clones derived from rats afflicted with AA. T cell clone A2b, which has been shown to be arthritogenic secreted low amounts of IFN-gamma and its Ag-specific proliferation was inhibited by IFN-gamma. In contrast, clone A2c, which can inhibit the development of AA, produced high amounts of IFN-gamma and its proliferation was increased by IFN-gamma. In vivo administration of IFN-gamma 24 h before CFA caused an enhancement of arthritis, whereas giving IFN-gamma 24 to 48 h after CFA suppressed the disease. Administration of IFN-gamma between day +4 to +12 or between day +12 to +24 increased the severity of the first phase of the disease, but had no effect later. Administration of DB-1 1 to 2 days before adjuvant or between day +4 to +8 substantially decreased the disease, whereas DB-1 given from day +12 to +24 significantly enhanced it. Taken together, these results illustrate the heterogeneity of IFN-gamma in autoimmune arthritis and suggest a rational explanation for the possibly conflicting reports regarding the role(s) and effects of IFN-gamma in autoimmune processes. The multistage nature of T cell-mediated autoimmune arthritis may be due to the predominance of distinct T cell populations at different stages of the disease. The differences in the biologic activities of these T cells may be due to their patterns of lymphokine production.
Jacob
C O
CO
Department of Microbiology, Stanford University School of Medicine, CA 94305.
Holoshitz
J
J
Van der Meide
P
P
Strober
S
S
McDevitt
H O
HO
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001168:Arthritis / Q000209:etiology*; D001169:Arthritis, Experimental / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D007371:Interferon-gamma / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D007371:Interferon-gamma; D005620:Freund's Adjuvant