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Maillet I, Schnyder-Candrian S, Couillin I, Quesniaux VF, Erard F, Moser R, Fleury S, Kanda A, Dombrowicz D, Szymkowski DE, Ryffel B (2011)

Posted on January 1, 2011 by alden

Rationale: TNF is a pleiotropic cytokine consisting of soluble and transmembrane forms with distinct roles in inflammation and immunity. TNF is an important factor in allergic airway inflammation; however, the disparate functions of soluble (sol) and transmembrane ™ TNF in lung pathology are not well understood. Objectives: Our aim was to assess activities of solTNF and tmTNF in mouse models of allergic airway disease, and to evaluate efficacy of solTNF-selective inhibition. Methods: We used ovalbumin sensitization and challenge of TNF knockout, tmTNF knockin, and wild-type C57BL/6 mice to distinguish differences in airway inflammation and hyperreactivity mediated by solTNF and tmTNF. Functions of solTNF and tmTNF in hyperresponsive wild-type Balb/c mice were next assessed by comparing dominant-negative anti-TNF biologics, which antagonize solTNF yet spare tmTNF, to etanercept, a nonselective inhibitor of both TNF forms. Measurements and Main Results: Responses in transgenic C57BL/6 mice demonstrated that solTNF, not tmTNF, is necessary to drive airway inflammation. In Balb/c mice, dominant-negative TNF biologics administered during immunization decreased eosinophil and lymphocyte recruitment into bronchoalveolar space and lung parenchyma, reduced specific serum IgE, goblet cell hyperplasia, and eosinophilic inflammation, and suppressed methacholine-induced airway hyperreactivity. Levels of IL-5, CCL5/RANTES, CCL11/eotaxin and CCL17/TARC were also reduced in bronchoalveolar lavage. Dominant-negative TNFs reduced lung eosinophilia even when given only during antigen challenge. Conclusions: Selective inhibition of soluble TNF suppresses inflammation, hyperreactivity, and remodeling in transgenic and wild-type mouse models of allergic airway disease, and suggests possible safety advantages for therapies that preserve the immunoprotective functions of transmembrane TNF.