Neutralization of IFN_ defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice-

Authors
J. Pachlopnik Schmid, C.-H. Ho, F. Chrétien, J. M. Lefebvre, G. Pivert et al.

Lab
Institut National de la Santé et de la Recherche Médicale, Unité U768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Paris, France ; Université Paris Descartes, Faculté de Médecine de l'université René Descartes, Institut Féd

Journal
EMBO Molecular Medecine

Abstract
Hereditary haemophagocytic lymphohistiocytosis (HLH) is a fatal inflammatory disease and treatments currently may lead to serious side effects. There is a pressing need for effective, less toxic treatments for this disease. Previous reports have suggested that interferon _ (IFN_) has a role in the pathogenesis of HLH. Here, we report that blocking IFN_ had a therapeutic effect in two different murine models of human hereditary HLH (perforin-deficient and Rab27a-deficient mice, both infected with lymphocytic choriomeningitis virus). Therapeutic administration of an anti-IFN_ antibody induced recovery from haemophagocytosis in both genetic models, as evidenced by increased survival in perforin-deficient mice and correction of blood cytopenia, moderation of body temperature changes, decreased cytokinaemia, restoration of splenic architecture and reduced haemophagocytosis in the liver of both murine models. Involvement of the central nervous system in Rab27a-deficient mice was prevented by anti-IFN_ therapy. Hepatic T-cell infiltrates and virus persisted, with no detectable harm during the time course of these studies. These data strongly suggest that neutralization of IFN_ could be used in humans to safely alleviate the clinical manifestations of haemophagocytosis.