Engraftment of cutaneous fibroblasts within synovial membrane in a nonhuman primate: short-term results.
OBJECTIVE
Gene therapy using cells as vectors to achieve secretion of therapeutic proteins may hold promise in the treatment of chronic diseases. Cell-based gene therapy with xenogeneic cells secreting antiinflammatory cytokines (IL-4, IL-13, or IL-1 receptor type II) has been found effective in mice with collagen-induced arthritis (CIA), a model for human rheumatoid arthritis. Autologous cells engineered to produce antiinflammatory cytokines were also effective in the mouse CIA model. In all these experiments, the cells were grafted into the subcutaneous tissue of the back, resulting in systemic treatment. To evaluate the feasibility of cell-based gene therapy confined to the joints, we performed intraarticular injections of autologous cells in a rhesus monkey with CIA, a model more similar to human RA.


METHODS
We prepared ex vivo cultures of skin fibroblasts from the animal then transfected the cells with a plasmid carrying the lacZ gene. We injected these marker cells into metacarpophalangeal, metatarsophalangeal, and interphalangeal joints.


RESULTS
Kinetic evaluation of synovial tissue X-gal labeling, which reflected reported gene expression by skin fibroblasts present within the synovium, showed significant labeling by transfected cells up to 6 days after intraarticular injection. Xenogeneic fibroblasts (Chinese hamster ovary cells) injected intraarticularly were also detected within synovial specimens; however, labeling intensity was less marked than with autologous cells. Our findings establish the feasibility of skin fibroblast grafting into the synovium.


CONCLUSIONS
This preliminary study opens the door to studies of heterotopic autologous transfected cells for the treatment of CIA in monkeys by direct gene transfer within joints.
Bessis
Natacha
N
Inserm, Eri-18, F-93017, Bobigny, France. n.bessis@smbh.univ-paris13.fr
Lemeiter
Delphine
D
Laroche
Liliane
L
Fournier
Catherine
C
Huizinga
Tom
T
Brok
Herbert
H
't Hart
Bert
B
Boissier
Marie-Christophe
MC
D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D016466:CHO Cells / Q000637:transplantation; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000637:transplantation*; D005384:Finger Joint; D015316:Genetic Therapy / Q000379:methods*; D006085:Graft Survival; D006801:Humans; D007270:Injections, Intra-Articular / Q000379:methods*; D007763:Lac Operon; D008253:Macaca mulatta; D008662:Metacarpophalangeal Joint; D008683:Metatarsophalangeal Joint; D051379:Mice; D012867:Skin / Q000166:cytology; D000074402:Synovectomy; D014033:Toe Joint; D014162:Transfection / Q000379:methods*; D014182:Transplantation, Autologous; D016896:Treatment Outcome