Enhancement of human natural killer cell function by the combined effects of tumor necrosis factor α or interleukin-1 and interferon-α or interleukin-2

The current studies examined the potential for additive or synergistic augmentation of human natural killer (NK) function by combined stimulation with tumor necrosis factor α (TNF-α) or interleukin-1 (IL-1) and interferon-α (IFN-α) or IL-2. The modest augmentative effect of preincubation with either IL-1 or TNF-α alone was most consistently shown when killing of an NK-resistant target was examined. Preincubation with the combination of IL-1 and TNF-α caused no additive effect on NK function. Following preincubation with IL-1 and IL-2 or TNF-α and IL-2, marked enhancement of NK activity was noted, particularly when lysis of the NK-resistant target Cur was assessed. Killing of K562 targets was more markedly augmented by costimulation with TNF-α and IL-2 than with IL-2 alone or the combination of IL-1 and IL-2. Finally, TNF-α in combination with either TNF-α or IL-1 markedly enhanced Cur lysis, whereas interferon-γ failed to augment IL-1- or TNF-α-enhanced tumor lysis. These findings demonstrate the separate and cooperative effects on human NK function of TNF-α or IL-1 in combination with IL-2 or TNF-α and suggest that the appropriate combinations of such agents may serve as the basis for in vivo multiagent immunotherapeutic regimens.