Successful gene therapy via intraarticular injection of adenovirus vector containing CTLA4IgG in a murine model of type II collagen-induced arthritis.
We previously constructed an adenovirus vector carrying a gene encoding a soluble form of fusion protein, consisting of the extracellular portion of cytotoxic lymphocyte antigen 4 (CTLA4) and the Fc portion of human immunoglobulin G1 (Adex1CACTLA4IgG). Murine type II collagen-induced arthritis (CIA) was treated with Adex1CACTLA4IgG. A single intraarticular injection of 1 x 10(5) PFU was able to support serum CTLA4IgG at more than 10 microg/ml for at least 12 weeks and was able to inhibit the CIA clinically and histologically. In contrast, intravenous, intramuscular, or subcutaneous injection of 1 x 10(5) PFU was unable to support a significant level of serum CTLA4IgG and thus was unable to inhibit the development of arthritis. Thus, we demonstrated that (1) a low-dose intraarticular injection of Adex1CACTLA4IgG was effective in delaying the onset of CIA and reducing the severity of arthritis; (2) an intraarticular (knee joint) injection of Adex1CACTLA4IgG effectively blocked the development of arthritis in distal paws; (3) the inhibitory effect of Adex1CACTLA4IgG lasted at least up to 20 weeks; (4) although serum CTLA4IgG at more than 10 microg/ml persisted for at least 12 weeks, mice treated by intraarticular injection of Adex1CACTLA4IgG were not anergic to adenovirus and were able to mount antibody responses against various antigens.
Ijima
K
K
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, 060-0815 Sapporo, Japan.
Murakami
M
M
Okamoto
H
H
Inobe
M
M
Chikuma
S
S
Saito
I
I
Kanegae
Y
Y
Kawaguchi
Y
Y
Kitabatake
A
A
Uede
T
T
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D060908:CTLA-4 Antigen; D003094:Collagen / Q000008:administration & dosage / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007113:Immunity, Innate / Q000235:genetics; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D007270:Injections, Intra-Articular; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D051379:Mice; D008811:Mice, Inbred DBA; D012720:Severity of Illness Index
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D000069594:Abatacept; D003094:Collagen