临床与实验药理学杂志

抽象的

A Sub Acute Immunotoxicity Study in G?ttingen Minipigs? with the Immunosuppressive Compounds Cyclosporin A and Dexamethasone

Geertje JD van Mierlo *,C Frieke Kuper ,Mary-Lène de Zeeuw-Brouwer ,Marcel A Schijf ,Joost P Bruijntjes ,Marlies Otto ,Niels- Christian Ganderup ,André H Penninks

Introduction: There is a growing interest in the minipig as a non-rodent species in the safety assessment of (bio) pharmaceuticals and (agro) chemicals. For (bio) pharmaceuticals the need to evaluate the potential adverse effects on the immune system is an increasingly important aspect of safety evaluation. In the present study, cyclosporin A and Dexamethasone were used as model compounds to examine whether the regulatory endpoints requested for immunotoxicity testing can be tested in the Göttingen minipig.
Methods: Minipigs were treated with vehicle, 20 mg/kg/day cyclosporine A or 0.4 mg/kg/day dexamethasone for 39 (males) or 40 (females) consecutive days. Clinical signs, body weight, hematology, lymphocyte subset analysis in peripheral blood mononuclear cells, Natural Killer cell activity, primary and secondary antibody response and Delayed Type Hypersensitivity response against Keyhole Limpet Hemocyanin (KLH), ex vivo mitogen-induced lymphocyte proliferation, examination at necropsy for gross macroscopic changes, weights and histopathology of lymphoid organs were used as criteria for evaluation of immunotoxic effects.
Results: Most parameters measured were implemented successfully in the minipig. Cyclosporin A treatment of minipigs had a slight effect on thymus weight, white blood cell counts and Keyhole Limpet Hemocyanin specific IgM responses. Clear effects were observed on mitogen-induced proliferation, Keyhole Limpet Hemocyanin specific IgG responses and Delayed Type Hypersensitivity response. Dexamethasone treatment resulted in decreased body weight, white blood cell counts, proliferative response to mitogen stimulation, Natural Killer cell activity and thymus weight. Keyhole Limpet Hemocyanin specific antibody responses were unaffected or slightly increased after dexamethasone treatment.
Discussion: With few exceptions, results obtained with cyclosporine A and dexamethasone in the minipig was in accordance with those presented for other species in the literature. Overall, the results presented in this article indicate that the minipig has potential to serve as an alternative non-rodent species for immunotoxicity testing as part of the safety assessment of (bio) pharmaceuticals and chemicals.