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William S. Rowe Division of Rheumatology, Children’s Hospital Medical Center, Cincinnati, OH 45229
Viral IL-10 (vIL-10) and soluble TNF receptor (sTNFR) are
anti-inflammatory proteins that can suppress collagen-induced
arthritis (CIA). These and related proteins have shown efficacy in the
treatment of human rheumatoid arthritis; however, neither alone is able
to completely suppress disease. Furthermore, they have short
half-lives, necessitating frequent administration. To determine the
ability of these proteins to act synergistically following gene
transfer, arthritis was induced in DBA/1 male mice by immunization with
type II collagen on days 0 and 21. Mice were injected i.v. either
before disease onset (day 20) or after disease onset (day 28) with
1010 particles of adenovirus encoding vIL-10, a soluble TNF
receptor-IgG1 fusion protein (sTNFR-Ig), a combination of both vectors,
or a control vector lacking a transgene. Significant synergism was
observed with the combination of vIL-10 and sTNFR-Ig, with a
substantial reduction in both the incidence and severity of disease as
well as inhibition of progression of established disease. sTNFR-Ig
alone had no effect on CIA. vIL-10 alone inhibited disease when given
before disease onset, but had minimal effect on established disease.
Both proteins inhibited spleen cell proliferation and IFN-
secretion
in response to stimulation with type II collagen, but only vIL-10
reduced the synovial mRNA levels of the proinflammatory cytokines
IL-1ß, TNF-
, and IL-6. These findings demonstrate that vIL-10 and
sTNFR-Ig act synergistically in suppressing CIA and suggest that gene
transfer offers a potential therapeutic modality for the treatment of
arthritis.
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