Down-regulation of Th1-mediated pathology in experimental arthritis by stimulation of the Th2 arm of the immune response.
OBJECTIVE
To assess whether systemic administration of recombinant interferon-gamma (rIFN gamma), a proinflammatory cytokine that influences the differentiation of naive T cells into Th1 cells, promotes the induction of arthritis in DBA/1 mice immunized with type II collagen (CII) in Freund's incomplete adjuvant (IFA) and to determine the antiarthritic effect of treatment with CII in IFA.


METHODS
DBA/1 mice were immunized with CII in IFA and injected intraperitoneally with rIFN gamma (8,000 units/mouse/day) or with recombinant interleukin-12 (rIL-12; 100 ng/mouse/day). In another experiment, mice were immunized with CII in Freund's complete adjuvant (CFA) and treated with a single dose of CII in IFA on the day of immunization or on the day of disease onset. Mice were monitored to assess the effect of the treatment on the severity of disease. Th1/Th2 cytokines and anti-CII antibodies were measured by enzyme-linked immunosorbent assay.


RESULTS
The administration of rIL-12 or rIFN gamma to mice immunized with CII in IFA restored the Th1 response and resulted in the development of arthritis. We then determined whether immunization with CII in IFA had the capacity to prevent and/or ameliorate collagen-induced arthritis. A single intraperitoneal injection of CII in IFA prevented arthritis when given at the time of immunization with CII in CFA and reduced disease severity when given at the time of arthritis onset. The administration of CII in IFA resulted in a profound down-regulation of IFN gamma production and an up-regulation of IL-10 in cultures of draining lymph node cells.


CONCLUSIONS
These findings demonstrate that it is possible to deflect an ongoing pathogenic Th1 response to an antigen by reimmunization of the same antigen with a Th2-polarizing adjuvant.
Mauri
Claudia
C
Center for Rheumatology Research, Windeyer Institute of Medical Sciences, University College London, London, UK. c.mauri@ucl.ac.uk
Feldmann
Marc
M
Williams
Richard O
RO
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002417:Cattle; D024043:Collagen Type II / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D015536:Down-Regulation; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D007114:Immunization; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D024043:Collagen Type II; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D005620:Freund's Adjuvant