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*
Department of Medicine, Section of Rheumatology, and Departments of
Immunology/Microbiology and
Orthopedic Surgery and Biochemistry, Rush Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612
In animal models of arthritis induced with Ags or infectious
agents, disease severity correlates with a dominant Th1-type response
characterized by a higher ratio of IFN-
to IL-4. Analysis of BALB/c
mice revealed a genetic predisposition toward developing
CD4+ Th2-type responses. The bias toward an IL-4-dominant
response in BALB/c mice protects mice from severe Lyme-induced
arthritis and spontaneous autoimmune disease. Since BALB/c mice
immunized with proteoglycan develop severe arthritis, we were
interested in testing whether arthritis is associated with a Th2-type
response and thus is different from other arthritic models. BALB/c mice
immunized with proteoglycan generated a higher ratio of IFN- to IL-4
that peaks at the onset of arthritis. We investigated whether when Th1
cells were dominant, disease outcome could be modified with
pharmacological amounts of Th2 cytokines. Treatment with IL-4 prevented
disease and induced a switch from a Th1-type to a Th2-type response.
Proinflammatory cytokine mRNA transcripts were reduced in joints of
cytokine-treated mice. Th2 cytokine therapy at the time of maximum
joint inflammation also suppressed symptoms of disease. Despite the
predisposition of BALB/c mice to a Th2-type response,
proteoglycan-induced arthritis is a Th1-type disease. The effectiveness
of IL-4 treatment was particularly striking because in other models of
arthritis, treatment in a similar manner with IL-4 was not sufficient
to inhibit arthritis. The effective control of arthritis and the switch
from a Th1 to Th2 response suggest that levels of endogenous IL-4 in
BALB/c mice may increase their responsiveness to Th2 cytokine
therapy.
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