Successful treatment of autoimmunity in mrl/1 mice with ls‐2616, a new immunomodulator

Abstract

Autoimmune MRLlI mice were treated with a recently developed substance with immunomodulating properties, LS-2616. Treatment was initiated at the age of 8 weeks, before the onset of clinically apparent disease, and at 16 weeks of age, after development of established lupus disease. Beneficial therapeutic effects were obtained, even when LS-2616 was administered at the lowest dose tested (1 mglmouselweek) to 16-week-old mice. The effects of LS-2616 on longevity, as well as on development of lymphadenopathy, splenomegaly, glomerulonephritis, and vasculitis, were pronounced and were comparable with those of cyclophosphamide. The results obtained suggest a potential role for LS-2616 in the treatment of autoimmune disease in humans.MRL-lprllpr (MRLl1) mice spontaneously develop a severe autoimmune disease which is characterized by massive generalized lymphadenopathy, arthritis, arteritis, and immune complex-mediated glomerulonephritis. Serologic abnormalities comprise hypergammaglobulinemia, occurrence of antibodies against native DNA, rheumatoid factor, and circulating immune complexes. The MRL/l strain may thus be regarded as a model for human systemic lupus erythematosus (SLE) and rheumatoid arthritis (1,2). Studies of MRL/I mice and other murine models of SLE, e.g., the New Zealand blacklNew Zealand white mouse model, have significantly contributed to our understanding of immunologic mechanisms also relevant to human autoimmunity. Furthermore, the above-mentioned autoimmune mouse strains have been used to document possible therapeutic effects of new compounds (3,4).We describe here the effects of a newly synthesized, immunomodulating chemical compound, LS-2616 (5). Treatment of MRLll mice with LS-2616 was initiated at different stages of disease, and its effects on survival, development, and severity of glomerulonephritis, vasculitis, and lymphadenopathy were studied. The effects of LS-2616 were compared with those of cyclophosphamide, a pharmacologic compound with well-documented cytotoxic properties. MATERIALS AND METHODSMice. MRLl1 mice, purchased from Jackson Laboratories (Bar Harbor, ME), were bred and maintained in the animal facilities of the Department of Medical Microbiology, University of Goteborg. Animals were randomly selected, virgin MRLll females.Procedures. Proteinuria was determined by means of Albustix (Ames, Elkhart, IN). Serum levels of antibodies against native DNA were measured by the indirect immunofluorescence method using Crithidiu luciliue as substrate (6). Serum levels of IgG were measured by radial immunodiffusion technique (7).

What can we learn about rheumatoid arthritis from animal models?

“…Thus, one example of the different effects in these two situations occurred after treatment of CIA in rats with cyclosporin, where prophylactic treatment (from immunization and onwards) could prevent disease, whereas cyclosporin treatment from the time of onset of the disease enhanced disease development [41]. A similar effect on heterologous CIA in rats was recently noted for an experimental drug, Linomide, previously shown to have a beneficial effect in MRL lpr/lpr mice [82] and which had paradoxical effects similar to cyclosporin A when given before and after the onset of disease [55]. From these data one should thus encourage use of models with a slow and chronic course where therapy instituted after disease onset can be readily evaluated; as discussed previously, it is feasible that the homologous CIA may represent the best current model in this respect.…”

Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice

“…In MRL/1 mice the impact of sex on disease progression is less striking compared with that of NZB/W mice. However, the life span of female MRL/I mice is slightly reduced and autoantibody formation is enhanced compared with males , Warren et al, 1984 (Carlsten et al, 1989a,b) and, therefore, we chose s.c. injection of oestradiol in order to obtain more physiological serum hormone levels (Tarkowski et al, 1986b). Furthermore, Shear et al, (1983) demonstrated that castration per se of young male MRL/l mice resulted in retarded mortality.…”

Dissolution rate-limited absorption and complete bioavailability of roquinimex in man

“…Three formulations of roquinimex were tested: (1) an intravenous solution of the sodium salt of roquinimex (corresponding to 0.5 mg ml − 1 free acid) dissolved in sterile physiological saline, (2) an oral solution of the sodium salt of roquinimex (corresponding to 0.5 mg ml − 1 free acid) dissolved in sterile water, and (3) a tablet formulation (Linomide ® , 5 mg). The in vitro dissolution rate of roquinimex from the tablet formulation was determined in 500 mL, 0.1 M hydrochloric acid at 70 rpm and 37°C using a USP Paddle Apparatus 2 (Prolabo, Paris, France).…”