Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept?
Tumor necrosis factor (TNF) is a critical component of both the antibacterially protective and the inflammatory responses against infections, particularly infections with intracellularly viable microorganisms. It is, therefore, not surprising that some treatment regimens that target TNF function have resulted in an increase in complications associated with infections due to such pathogens as Mycobacterium tuberculosis, Listeria monocytogenes, and Histoplasma capsulatum; organized granuloma formation is required to keep such infections under control. However, treatment with anti-TNF monoclonal antibodies (i.e., infliximab) has been associated with a higher incidence of granulomatous infections than has treatment with a TNF receptor (TNFR) p75 immunoglobulin G-fusion construct (i.e., etanercept). Three hypotheses concerning the mode of action of these 2 agents that might explain this difference are discussed here: differential induction of apoptosis or lysis in membrane TNF-expressing macrophages and T cells, differential inhibition of signaling via TNFRp55 and TNFRp75, and different net neutralizing capacities resulting from different pharmacologic properties.
Division of Molecular Infection Biology, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany. sehlers@fz-borstel.de
Stefan
S
Ehlers
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002634:Chemotaxis, Leukocyte; D000068800:Etanercept; D006099:Granuloma / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D000069285:Infliximab; D018124:Receptors, Tumor Necrosis Factor; D012306:Risk; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept