Binding and neutralization of soluble TNF-a is probably not the only activity mediated by infliximab. Indeed, in vitro assays have shown that infliximab also binds to membrane-bound TNF- and induces cell death (Scallon et al. 1995). However, clinical observations suggest that infliximab mediated cytotoxicity in vivo is limited. Infliximab infusions are very well tolerated and patients do not experience a cell lysis syndrome (Scallon et al. 1995). Similarly, the number of circulating mononuclear cells does not decrease following infliximab infusions. In contrast, programmed cell death (apoptosis) has been observed in Crohn's patients treated with infliximab within 24 h of a single infusion. In these patients a significant increase in the number of apoptotic T cells was noted in the lamina propria. Interestingly, infliximab dependent apoptosis of T cells appears to be restricted to activated T cells since in an in vitro experiment infliximab only lysed activated, but not resting, Jurkat (a T-cell line) cells (ten Hove et al. 2002). These experiments suggest that the efficacy of infliximab observed in chronic inflammatory conditions is not only mediated through the neutralization of TNF-a, but also through other activities like induction of cell death in selected cells.
membrane-bound forms of TNF-a soluble TNF-a membrane-bound TNF-a
Fig. 2.1. Bivalent interaction of infliximab with its ligand cross-links soluble and membrane-bound TNF-a (modified from Scallon B et al. 2002. J Pharmacol Exp Ther 301:418-426, with permission)
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