Administration of tumor necrosis factor alpha (TNF alpha) inhibitors after exposure to TNF alpha prevents development of the maximal biological effect: an argument for clinical treatment with TNF alpha inhibitors

Abstract

The cytokine tumor necrosis factor alpha (TNF alpha) is involved in the pathophysiology of a wide variety of diseases. Pretreatment with anti-TNF alpha antibodies has proven its success in animal models of disease. The question, however, whether intervention with anti-TNF alpha antibodies might be useful in the clinical situation in which TNF alpha is already produced is still unanswered. We therefore studied the relation between the duration of TNF alpha/TNF receptor interaction and the extent of the induced biological effects in two different in vitro systems: (1) the slowly induced cytotoxicity of the TNF-sensitive murine cell line L929, and (2) the rapid TNF alpha-induced expression of an adhesion molecule for the polymorphonuclear cell, ELAM-1 on human endothelial cells. The TNF alpha/TNF receptor interaction was interrupted at different times after onset of stimulation, either by washing away TNF alpha or by adding TNF alpha activity-blocking monoclonal antibody. To establish an optimal effect for both TNF alpha-induced cytotoxicity on L929 cells and TNF alpha-induced expression of ELAM-1 on human endothelial cells, the TNF receptor had to be occupied by TNF alpha for at least 30-60% of the full incubation period. This observation provides an argument that clinical intervention with TNF alpha inhibitors can be advantageous, even in a situation in which TNF alpha has already been released into the circulation.