The Interferon Refractory State: in Vivo and in Vitro Studies of Its Mechanism

Abstract

Interferon synthesis is followed by a period of refractoriness during which restimulation with inducer fails to elicit an interferon response. This period persisted in mice absolutely for 4 days and partially for 13 days; interferon was initially induced with Newcastle disease virus (NDV) and animals were restimulated with an unrelated viral inducer. The development of refractoriness was found to be a graded function of the amount of inducer given and interferon made. Exhaustion of interferon-producing capabilities did not cause the refractory state; it developed both in vivo and in vitro after doses of NDV which elicited a less than maximal response. Furthermore, after an amount of inducer was given which was insufficient to infect all cells with complete infectious virus, refractoriness developed in cultures. In both mice and L cells refractoriness lagged significantly behind maximal interferon production; it was not discernible for 12 to 24 hr after measurable interferon response. Using this delay in the onset of refractoriness, partial biologic separation of repressive activity from antiviral activity of interferon preparations was achieved. Pretreatment of L cell monolayers with 75 units/ml of interferon preparations, collected 36 hr after inoculation of inducer, repressed interferon synthesis to a decidedly greater degree than those collected at 8 hr. Pretreatment of L cell monolayers with small amounts of interferon, 2 units/ml, enhanced interferon production to NDV. These findings suggest a newly synthesized repressor as the mediator of the interferon refractory state.