Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer.
Autoimmune arthritides are characterized by an imbalance between pro- and anti-inflammatory cytokines. Viral IL-10 (vIL-10) shares many of the anti-inflammatory properties of mouse and human IL-10, but lacks their immunostimulatory properties and may therefore offer superior immunosuppression. Viral IL-10 has a short half-life; however, genetic modification of cells in vivo offers a potential means of achieving prolonged therapeutic titers. To determine the effects on collagen-induced arthritis of vIL-10 gene transfer, DBA/1 mice were administered i.v. or intra-articular injections of Av(vIL-10), a replication-deficient adenovirus encoding vIL-10. The i.v. injection of Av(vIL-10) before disease onset delayed the onset and reduced the severity of collagen-induced arthritis, but treatment of established disease was ineffective. The preventative effects were not due to decreased anti-type II collagen Ab production. Rather, T cells from mice treated with Av(vIL-10) demonstrated a decreased in vitro proliferative response to type II collagen, and a delay was observed in up-regulation of synovial mRNA for the proinflammatory cytokines IL-2 and IL-1beta. Intra-articular injection of Av(vIL-10) into knee joints did not reduce arthritis in the knees, but inhibited the development of arthritis in the paws. Humoral and cellular immune responses against Av(vIL-10) were observed. These results demonstrate that vIL-10 can significantly alter the course of autoimmune arthritis and emphasize the complexities of using gene transfer as a method of drug delivery for arthritis.
Ma
Y
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Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Thornton
S
S
Duwel
L E
LE
Boivin
G P
GP
Giannini
E H
EH
Leiden
J M
JM
Bluestone
J A
JA
Hirsch
R
R
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001169:Arthritis, Experimental / Q000453:epidemiology / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005620:Freund's Adjuvant; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage*; D007074:Immunoglobulin G / Q000096:biosynthesis; D015994:Incidence; D007270:Injections, Intra-Articular; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics*; D007719:Knee Joint / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000096:biosynthesis; D013997:Time Factors
D016207:Cytokines; D007074:Immunoglobulin G; D012333:RNA, Messenger; D016753:Interleukin-10; D003094:Collagen; D005620:Freund's Adjuvant