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*
Kennedy Institute of Rheumatology, London, United Kingdom; and
Department of Surgery, University of Limburg, Maastricht, The Netherlands
Collagen-induced arthritis (CIA) is an experimental model of
arthritis widely used to dissect the pathogenesis of human rheumatoid
arthritis and to identify potential therapeutic targets. Among these,
TNF-
has been recognized to play an important role. Here we
investigate the feasibility and therapeutic efficacy of prolonged
blockade of TNF- activity through the adenovirus-mediated gene
delivery of a dimeric chimeric human p55 TNFR-IgG fusion protein and
compare it to protein therapy in established CIA. A single i.v.
administration of the replication-deficient adenovirus yielded
microgram serum levels of the chimeric fusion protein and ameliorated
CIA for 10 days. Subsequently, benefit was lost and a rebound to
greater inflammatory activity was observed despite the continual
presence of bioactive TNFR fusion protein. A similar trend was also
observed in mice injected directly with comparable amounts of a human
TNFR-IgG fusion protein, whereas the administration of a control
adenovirus-encoding ß-galactosidase or of a control human IgG1
protein did not significantly affect the disease course. The mechanisms
of the rebound of CIA were investigated, and augmented Ab
response to collagen type II and TNFR were identified as potential
causes. Our results confirm the feasibility of adenovirus-mediated gene
delivery of cytokine inhibitors in animal models of autoimmune diseases
for investigational purposes and highlight the importance of
prolonged studies. Further investigations are needed to optimize ways
of exploiting the potential of adenoviral gene therapy in
RA.
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