AN EX-VIVO METHOD FOR STUDYING INFLAMMATION IN CYNOMOLGUS MONKEYS - ANALYSIS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST

Nonhuman primates have been used as models for testing the role of int erleukin-1 (IL-1) in inflammatory diseases, including endotoxemia. The objective of this investigation was to develop a reproducible and rap id method for in vivo evaluation of IL-1 antagonists using cynomolgus monkeys. IL-1 alone can induce many of the symptoms of endotoxemia in monkeys including fever, loss of appetite, and lethargy, however, test animals are slow to recover and may become desensitized to IL-1. We h ave developed an ex vivo method using whole blood for analysis of IL-1 antagonists administered in vivo to the monkeys and report here resul ts for the naturally occurring IL-1 receptor antagonist, IL-1ra. In th is procedure, animals are given an i.v. infusion of IL-1ra, and blood samples are taken preinfusion and during the infusion. The samples are incubated with or without IL-1 beta and the subsequent ex vivo induct ion of IL-6 determined. This allows analysis of the effects of in vivo pharmacodynamics on the efficacy of antagonists without exposing the test animals to IL-1. In this ex vivo protocol, each animal serves as its own control, eliminating from the assessment the large animal to a nimal variation observed with in vivo responses. By testing various do ses, we estimate that 50% inhibition of IL-1 induced IL-6 can be achie ved with an infusion of IL-1ra at 5 mu g/kg/15 min. This method allows simple and efficient analysis of inhibitors and antagonists of IL-1 a nd, potentially, other effecters. (C) 1996 Elsevier Science Inc.