C3-Tat/HIV-regulated intraarticular human interleukin-1 receptor antagonist gene therapy results in efficient inhibition of collagen-induced arthritis superior to cytomegalovirus-regulated expression of the same transgene.
OBJECTIVE
To achieve disease-inducible expression of recombinant antiinflammatory proteins in order to allow autoregulation of drug dose by natural homeostatic mechanisms.


METHODS
We compared the inducible 2-component expression system (C3-human immunodeficiency virus/transactivator of transcription [C3-Tat/HIV]) with the constitutive cytomegalovirus (CMV) promoter in the polyarticular collagen-induced arthritis (CIA) model in mice. DBA/1 mice were immunized with bovine type II collagen and were given boosters on day 21. On day 22, mice were injected intraarticularly with the adenoviral vectors AdCMVLuc, AdCMVhIL-1Ra, AdC3-Tat/HIV-Luc, or AdC3-Tat/HIV-hIL-1Ra. The injected knee joints and hind paws were then scored for signs of arthritis, and knee joint histology was compared.


RESULTS
The CMV-driven interleukin-1 receptor antagonist (IL-1Ra) expression resulted in a high constitutive expression and amelioration of CIA. C3-Tat/HIV-driven IL-1Ra expression could be detected only on days 24, 29, and 35. Fourteen days after injection of the vectors, CIA was significantly better inhibited by the C3-Tat/HIV-driven IL-1Ra expression compared with the CMV-driven IL-1Ra expression. Moreover, prevention of CIA in the knee joints also prevented CIA in the untreated hind paws.


CONCLUSIONS
Our data demonstrate for the first time the feasibility of an inducible expression system for local production of IL-1Ra for treatment of arthritis in the CIA model.
Bakker
A C
AC
Department of Rheumatology, University Medical Center Nijmegen, Geert Grooteplein 26-28, 6500 HB Nijmegen, The Netherlands.
van de Loo
F A J
FA
Joosten
L A B
LA
Arntz
O J
OJ
Varley
A W
AW
Munford
R S
RS
van den Berg
W B
WB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000628:therapy*; D003176:Complement C3 / Q000235:genetics*; D003587:Cytomegalovirus / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D007270:Injections, Intra-Articular; D053590:Interleukin 1 Receptor Antagonist Protein; D007719:Knee Joint / Q000473:pathology; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011401:Promoter Regions, Genetic / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
D003176:Complement C3; D015696:Gene Products, tat; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins; D008156:Luciferases