The therapeutic use of osmotic minipumps in the severe combined immunodeficiency (SCID) mouse model for rheumatoid arthritis.
OBJECTIVE
The viral gene transfer of interleukin 1 receptor antagonist (IL1ra) and interleukin 10 (IL10) into rheumatoid arthritis (RA) synovial fibroblasts (RASFs) has shown protective effects on cartilage destruction in the severe combined immunodeficiency (SCID) mouse model of RA. Nevertheless, side effects of viral transduction are possible and a number of cytokines or cytokine inhibitors are not available encoded in viral vehicles. As the production of viruses coding for bioactive proteins is cost and time intensive, we established an in vivo long-term release model using osmotic minipumps in the SCID mouse model for RA.


METHODS
Isolated RASFs were cultured for four passages and coimplanted together with human cartilage and an Alzet osmotic miniature pump model 2004, containing 200 microl of IL10 and IL1ra for 40 days in SCID mice. Implants were removed after 40 days and evaluated histologically. The actual rates of IL10 and IL1ra in murine serum were measured by ELISA.


RESULTS
Release of IL10 and IL1ra by the pumps was effective as both could be measured in significant amounts in the serum of the mice. IL10 and IL1ra release showed protective effects towards the coimplanted cartilage, similar to the adenovirally IL10/IL1ra-transduced RASFs. The mean (SD) invasion scores for the implants with the osmotic pumps were: invasion 0.7 (0.5), degradation 0.5 (0.3) (all parameters significant vs controls, p<0.05).


CONCLUSIONS
The results demonstrate that the combination of osmotic pumps with the SCID mouse model for RA can be used as approach for application and evaluation of cartilage-protective molecules. Furthermore, the effect of cartilage-protective cytokines is independent of the type of application.
Knedla
A
A
Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Giessen, Department of Rheumatology and Clinical Immunology, Kerckhoff-Klinik Bad Nauheim, Germany.
Riepl
B
B
Lefèvre
S
S
Kistella
S
S
Grifka
J
J
Straub
R H
RH
Gay
S
S
Schölmerich
J
J
Müller-Ladner
U
U
Neumann
E
E
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002358:Cartilage, Articular / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D015918:Infusion Pumps, Implantable; D053590:Interleukin 1 Receptor Antagonist Protein / Q000032:analysis / Q000235:genetics / Q000627:therapeutic use; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D014161:Transduction, Genetic / Q000295:instrumentation / Q000379:methods*
D053590:Interleukin 1 Receptor Antagonist Protein; D016753:Interleukin-10