Journal
EMBO MOLECULAR MEDICINE
Volume 1, Issue 2, Pages 112-124Publisher
WILEY
DOI: 10.1002/emmm.200900009
Keywords
haematology; haemophagocytic lymphohistiocytosis; IFN gamma; immunopathology; immunotherapy
Categories
Funding
- Institut National de la Santeet de la Recherche Medicale (INSERM)
- Agence Nationale de la Recherche [ANR-05-MIM-010, BLAN06-3_145379]
- Fondation pour la Recherche Medicale
- European Community [HEALTH-F2-2008-201461]
- Swiss Foundation for Grants in Medicine and Biology SSMBS (Swiss National Science Foundation) [1211/PASMA-110658/1]
- Fondazione Ettore e Valeria Rossi
- Walter und Gertrud Siegenthaler Stiftung
- MRC [G0900867] Funding Source: UKRI
- Medical Research Council [G0900867] Funding Source: researchfish
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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 gamma (IFN gamma) has a role in the pathogenesis of HLH. Here, we report that blocking IFN gamma 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 gamma 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 gamma 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 gamma could be used in humans to safely alleviate the clinical manifestations of haemophagocytosis.
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