Naslov
The effect of cyclosporin on chronic relapsing experimental allergic encephalomyelitis in rat

Autori
Zaputović, Luka

Izvornik
Periodicum biologorum (0353-9164) 88 (1986), Supplement 1/A; 347-349

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Encephalomyelitis; chronic; relapsing; experimental; allergic; Cyclosporin; Rat

Sažetak
Cyclosporin is a potent new immunosupressive agent. Although extracted as a fungal metabolite, its spectrum of antibiotic activity is limited only to a few viral, parasitic and fungal species (3, 4). Unexpectedly, it has been shown to elicit strong immunosupressive action both in vivo and in vitro (1, 2). The discovery of the immunosupressive properties of cyclosporin has given significant impulse to organ transplantation. A great number of autoimmune diseases represent the other possibility of its clinical use (7). As the prototipe experimental system for neuroimmunological disorders (6), experimental allergic encephalomyelitis (EAE) can be adopted for the selection of immune modulating compounds to be used in the therapy of established neurological autoimmune diseases in man. In our work we used a chronic relapsing form of EAE (CR-EAE) in juvenile rats (AOxDA)F1 hybrids as an experimental model. The prophylactic and therapetic effect of cyclosporin on occurence, severity of clinical signs and development of delayed hypersensitivity to encephalitogen has been investigated. The sensitization of animals was made by subcutaneous inoculation with 0, 1 ml of encephalitogenic emulsion in both back foot pads. The emulsion was prepared by homogenization of 10 g of calf brain white matter with 10 ml of sterile physological solution and 20 ml of complete Freund's adjuvant (CFA). The clinical course was followed for six months after sensitization. The rats were scored daily for symptoms of disease according to standard protocol: no symptoms = 0, flaccid tail = 1, hind leg weakness = 2, hind leg paralysis = 3, moribund state = 4. The development of delayed type hypersensitivity (DTH) to encephalitogen was followed by a skin test performed on the third, seventh, tenth and fifteenth day after sensitization. The PPD and emulsion of calf brain white matter (10 g) in sterile phisiological solution (30 g), but without CFA, were used as antigens. Additional skin tests were performed at eight and sixteen weeks after the sensitization. Cyclosporin was given orally in a dose of 20 mg/kg dissolved in olive oil. For the prophylaxis of CR-EAE rats were dosed daily for 20 days starting on the day before sensitization. For the therapy of CR-EAE we used rats as soon as they reached stage 2 or 3 of the disease. Diseased animals were treated daily for 10 consecutive days. At the same time the control animals were given only the vehicle. Care was taken to put food and water in the proximity of the paralyzed rats. All sensitized rats expressed CR-EAE in spite of treatment with the vehicle control in the inductive phase of the disease. However, stress-conditions prolonged the initial period and enlarged the survival from a usual 75% to 100%. DTH to encephalitogen already existed on the third day after sensitisation, growing up until the ninth day and weakening just at the time of disease appearance (Figure 1). These results strongly suggest that DTH-cells can play an important role in the pathogenesis of CR-EAE. DTH-reactivity was also positive during the stabile remission 8-16 weeks from sensitization. Prophylactic treatment with cyclosporin resulted in the total prevention of CR-EAE. Therapeutic treatment of the already developed disease with the same oral dose resulted in a rapid regression of clinical signs, although sudden death occured in 50 % of the animals, 4-6 days after the last administration. The development of DTH-reactivity during the inductive phase of the disease is completely inhibited by prophylactic use of cyclosporin, remaining negative 8-16 weeks from sensitization. In terapeutically treated animals, DTH-reactivity was suppressed 8 weeks from sensitization, but positive after 16 weeks. Therefore, it seems likely that therapeutic treatment only temporarily suppressed, while prophylactic use of the drug completely inhibited the development of T-cell mediated hypersensitivity to encephalitogen. The beneficial effect of cyclosporine in our model can be explained by selective action on activation and/or expansion of T-lymphocyte subsets with different functions. In this case, the sensitive balance between helper and suppressor T-lymphocyte subsets would be displaced to the latter side. Sudden death in 50% of therapeutically treated rats perhaps occurred because of relatively stronger cyclosporin toxicity in animals with developed clinical signs of CR-EAE. The transient fall of body weight during the immunosupression can also be the result of drug toxicity (5, 8).

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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