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Effect of tumour necrosis factor alpha in vivo on human granulocyte oxidative metabolism
1Department of Dermatology, University of Freiburg, Federal Republic of Germany.
Abstract:
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 continuous daily infusions with TNF alpha induce a hyposensitization of PMN oxidative metabolism.
Insights
Tumor necrosis factor alpha (TNF alpha) therapy in melanoma patients alters polymorphonuclear neutrophil (PMN) responses. Daily TNF alpha may lead to hyposensitization of PMN oxidative metabolism during treatment.
Area of Science:
- Immunology
- Oncology
- Cellular Metabolism
Background:
- Tumor necrosis factor alpha (TNF alpha) is known to stimulate polymorphonuclear neutrophil (PMN) oxidative metabolism in vitro.
- Pre-incubation with TNF alpha can alter PMN responses to subsequent stimuli.
- Investigating in vivo effects of TNF alpha therapy on PMN function is crucial for understanding treatment responses and potential side effects.
Purpose of the Study:
- To investigate the in vivo response of PMN oxidative metabolism to various stimuli in patients with metastasizing malignant melanoma receiving TNF alpha therapy.
- To assess changes in PMN function during a 5-day course of daily TNF alpha injections.
- To determine if continuous TNF alpha administration leads to altered PMN responsiveness or hyposensitization.
Main Methods:
- Patients with metastasizing malignant melanoma received daily bolus injections of recombinant human TNF alpha for 5 days.
- Blood samples were collected on days 1-4 and day 8.
- Lucigenin-enhanced chemiluminescence (CL) measured PMN oxidative metabolism following stimulation with TNF alpha, TNF beta, GM-CSF, PMA, opsonized zymosan, and f-met-leu-phe.
Main Results:
- Significant increases in CL responses were observed upon stimulation with TNF alpha, TNF beta, and PMA from day 1 to day 3.
- PMN responses returned to baseline by day 4, with a significant decrease observed on day 8 for TNF alpha, TNF beta, and GM-CSF.
- Stimulation with f-met-leu-phe showed a delayed peak response on day 4, returning to baseline by day 8.
Conclusions:
- In vivo TNF alpha administration induces significant, time-dependent changes in PMN responsiveness to various stimuli.
- Continuous daily TNF alpha infusions may lead to a hyposensitization of PMN oxidative metabolism.
- These findings highlight the dynamic impact of TNF alpha therapy on innate immune cell function in cancer patients.