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

The cytokine tumor necrosis factor α (TNFα) is involved in the pathophysiology of a wide variety of diseases. Pretreatment with anti-TNFα antibodies has proven its success in animal models of disease. The question, however, whether intervention with anti-TNFα antibodies might be useful in the clinical situation in which TNFα is already produced is still unanswered. We therefore studied the relation between the duration of TNFα/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 TNFα-induced expression of an adhesion molecule for the polymorphonuclear cell, ELAM-1 on human endothelial cells. The TNFα/TNF receptor interaction was interrupted at different times after onset of stimulation, either by washing away TNFα or by adding TNFα activity-blocking monoclonal antibody. To establish an optimal effect for both TNFα-induced cytotoxicity on L929 cells and TNFα-induced expression of ELAM-1 on human endothelial cells, the TNF receptor had to be occupied by TNFα for at least 30-60% of the full incubation period. This observation provides an argument that clinical intervention with TNFα inhibitors can be advantageous, even in a situation in which TNFα has already been released into the circulation. © 1992.