The viable motheaten (mev) mouse--a new model for arthritis.
Homozygous mev mice are first identified at the age of 3-4 days by focal depigmentation of the skin, followed by patchy absence of hair and by necrotic lesions on paws, tail and ears. Of particular interest are the inflammatory reactions in the paws of these animals which consist mainly of polymorphonuclear and mononuclear cell infiltration in the subcutaneous tissue extending to the periosteum and joint, resulting in focal destructive arthritis and osteomylitis. These lesions are to some extent reminiscent of an acute form of rheumatoid-like arthritis. Since mev mice are sterile, a limited number of symptomatic offspring can be obtained by cross-breeding their heterozygous siblings which are phenotypically not distinguishable from mice lacking this mutation. In order to produce a sufficient number of diseased animals for performing pharmacological studies, we have established a model by transferring this disease in lethally irradiated, 8- to 10-week-old syngeneic mice which were grafted with mev spleen cells. Such reconstituted recipients develop first inflammatory symptoms of the paws 2 to 3 weeks after cell transfer. The arthritic inflammation finally affects all paws and toes by 30 to 50 days. This procedure increased the number of mev-like mice expressing arthritis, allowing assessment of the effects of standard reference drugs used in the therapy of rheumatoid arthritis (RA). The immunosuppressants cyclosporin and rapamycin and the steroid dexamethasone at therapeutic concentrations exert a strong inhibitory effect on the development of arthritis in this novel model. In contrast, the non-steroidal anti-inflammatory drug phenylbutazone shows only a moderate effect. These results indicate the particular sensitivity of this model for efficacy of potentially new therapeutic but non-cytostatic compounds for clinical use.
Immunology Department, Sandoz Pharma Ltd, Basel, Switzerland.
J
J
Kovarik
L
L
Kuntz
B
B
Ryffel
J F
JF
Borel
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D005528:Foot / Q000473:pathology; D007665:Ketotifen / Q000627:therapeutic use; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010653:Phenylbutazone / Q000627:therapeutic use; D011090:Polyenes / Q000627:therapeutic use; D011828:Radiation Chimera; D020123:Sirolimus; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
D011090:Polyenes; D003907:Dexamethasone; D016572:Cyclosporine; D010653:Phenylbutazone; D020123:Sirolimus; D007665:Ketotifen