Dominant-negative tumor necrosis factor protects from Mycobacterium bovis Bacillus Calmette Guérin (BCG) and endotoxin-induced liver injury without compromising host immunity to BCG and Mycobacterium tuberculosis.
BACKGROUND
Tumor necrosis factor (TNF) is associated with the development of inflammatory pathologies. Antibodies and soluble TNF (solTNF) receptors that neutralize excessive TNF are effective therapies for inflammatory and autoimmune diseases. However, clinical use of TNF inhibitors is associated with an increased risk of infections.


METHODS
A novel dominant-negative (DN) strategy of selective TNF neutralization, consisting of blocking solTNF while sparing transmembrane TNF (tmTNF), was tested in mouse models of mycobacterial infection and acute liver inflammation. XENP1595, a DN-TNF biologic, was compared with etanercept, a TNF receptor 2 (TNFR2)-IgG1 Fc fusion protein that inhibits murine solTNF and tmTNF.


RESULTS
XENP1595 protected mice from acute liver inflammation induced by endotoxin challenge in Mycobacterium bovis bacillus Calmette-Guérin (BCG)-infected mice, but, in contrast to etanercept, it did not compromise host immunity to acute M. bovis BCG and Mycobacterium tuberculosis infections in terms of bacterial burden, granuloma formation, and innate immune responses.


CONCLUSIONS
A selective inhibitor of solTNF efficiently protected mice from acute liver inflammation yet maintained immunity to mycobacterial infections. In contrast, nonselective inhibition of solTNF and tmTNF suppressed immunity to M. bovis BCG and M. tuberculosis. Therefore, selective inhibition of solTNF by DN-TNF biologics may represent a new therapeutic strategy for the treatment of inflammatory diseases without compromising host immunity.
Olleros
Maria L
ML
Department of Pathology and Immunology, Centre Medical Univeristaire, Hopitaux Universitaires de Geneve, University of Geneva, Switzerland.
Vesin
Dominique
D
Lambou
Agathe F
AF
Janssens
Jean-Paul
JP
Ryffel
Bernhard
B
Rose
Stéphanie
S
Frémond
Cécile
C
Quesniaux
Valérie F
VF
Szymkowski
David E
DE
Garcia
Irene
I
D000818:Animals; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008107:Liver Diseases / Q000517:prevention & control; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*
D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595; D000068800:Etanercept