EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA INVIVO ON HUMAN GRANULOCYTE OXIDATIVE-METABOLISM

Tumour necrosis factor alpha (TNF-alpha) effectively stimulates the oxidative metabolism of human PMN in vitro. Moreover, preincubation of PMN with TNF-alpha has been shown to result in an altered response of the target cells to subsequent stimulation. In the present study the response of PMN to stimulation in vitro was investigated in patients with metastasizing malignant melanoma receiving bolus injections of recombinant human TNF-alpha as therapy. TNF-alpha was given daily for 5 days. Blood samples were taken prior to TNF-alpha administration on days 1 to 4 and on day 8. Lucigenin-enhanced chemiluminescence (CL) was used as a sensitive measure of granulocyte oxidative metabolism. PMN were stimulated with TNF-alpha, TNF-beta, GM-CSF, PMA, opsonized zymosan and f-met-leu-phe. A significant increase in CL responses was detected upon stimulation with TNF-alpha, TNF-beta and PMA from day 1 to day 3, whereas no significant changes were observed for the background activity or when GM-CSF or opsonized zymosan were used as stimuli. On day 4 all CL responses returned to the day 1 starting level. A further significant decrease was observed on day 8 upon stimulation with TNF-alpha, TNF-beta and GM-CSF. In contrast, the effect induced by f-met-leu-phe reached a maximum on day 4, but the CL response was found to be at the starting level on day 8. The results indicate that TNF-alpha induces significant changes in PMN response to distinct stimuli in vivo. Moreover, it may be possible that continous daily infusions with TNF-alpha induce a hyposensitization of PMN oxidative metabolism.