Related Experiment Videos
Kinetics of soluble TNF-receptors and soluble adhesion molecules ICAM-1, E-selectin and VCAM-1 under systemic rhTNF
M W Boehme1, R Waldherr, A Kist
1Department of Internal Medicine IV, University of Heidelberg, Germany.
Abstract:
Cytostatic as well as cytotoxic effects of tumour necrosis factor alpha (TNF-alpha) therapy have been shown in vitro and in experimental in vivo models. Nevertheless, the mechanism of anti-tumour activity in humans in vivo remains unclear. To determine the role of the vascular lining endothelial cells as important mediators of several immunological interactions, we investigated changes in the levels of the soluble endothelial cell adhesion molecules intercellular adhesion molecule 1, E-selectin and vascular cell adhesion molecule 1 as well as of soluble TNF receptors I and II during systemic therapy with recombinant human rhTNF-alpha (rhTNF-alpha). All tests were performed by enzyme-linked immunosorbent assays (ELISAs). The clinical efficacy of the intravenous rhTNF-alpha therapy was poor. Only one patient with isolated intraarterial limb perfusion had a delayed, marked, but only temporary necrosis of tumour cells. In contrast, we found a marked, significant and (during therapy) undulating augmented increase in the levels of soluble adhesion molecules as well as of the soluble TNF receptors. Taken together, these data support the hypothesis that a sufficient tumour-specific cellular immunity is required to achieve a clinically apparent efficacy of systemic rhTNF-alpha therapy in addition to cytokine-dependent inducible activation mechanisms. In this context, the vascular lining endothelial cells might play an important role as mediators of the complex immunological antitumoral activity.
Insights
Tumor necrosis factor alpha (TNF-alpha) therapy showed poor clinical efficacy in humans. Increased soluble adhesion molecules and TNF receptors suggest a need for cellular immunity alongside cytokine activation for anti-tumor effects.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Tumor necrosis factor alpha (TNF-alpha) exhibits anti-tumor effects in vitro and in animal models.
- The precise mechanism of TNF-alpha's anti-tumor activity in humans remains incompletely understood.
Purpose of the Study:
- To investigate the role of endothelial cells in TNF-alpha therapy by measuring soluble adhesion molecules and TNF receptors.
- To correlate changes in these markers with clinical outcomes of TNF-alpha treatment.
Main Methods:
- Systemic therapy with recombinant human TNF-alpha (rhTNF-alpha) was administered.
- Levels of soluble intercellular adhesion molecule 1, E-selectin, vascular cell adhesion molecule 1, and soluble TNF receptors I and II were measured using enzyme-linked immunosorbent assays (ELISAs).
Main Results:
- Clinical efficacy of intravenous rhTNF-alpha therapy was generally poor, with only temporary tumor necrosis in one patient receiving isolated limb perfusion.
- A significant, undulating increase in soluble adhesion molecules and soluble TNF receptors was observed during therapy.
Conclusions:
- Effective anti-tumor response to systemic rhTNF-alpha therapy likely requires robust tumor-specific cellular immunity in addition to cytokine-induced activation.
- Endothelial cells may act as crucial mediators in the complex immunological anti-tumor activity induced by TNF-alpha.