Protection from Inflammatory Organ Damage in a Murine Model of Hemophagocytic Lymphohistiocytosis Using Treatment with IL-18 Binding Protein
Laura Chiossone,Sandra Audonnet,Bruno Chetaille,Lionel Chasson,Lionel Chasson,Catherine Farnarier,Yael Berda-Haddad,Stefan Jordan,Ulrich H. Koszinowski,Marc Dalod,Marc Dalod,Karin Mazodier,Daniela Novick,Charles A. Dinarello,Eric Vivier,Gilles Kaplanski +15 more
Reads0
Chats0
TLDR
Data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.Abstract:
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.read more
Citations
More filters
Journal ArticleDOI
Adult haemophagocytic syndrome
Manuel Ramos-Casals,Pilar Brito-Zerón,Armando López-Guillermo,Munther A. Khamashta,Xavier Bosch +4 more
TL;DR: Analysis of the genetic and molecular pathophysiology of these syndromes have improved the understanding of the crosstalk between lymphocytes and histiocytes and their regulatoty mechanisms, and it is essential to initiate appropriate treatment and improve the quality of life and survival of patients with this challenging disorder.
Journal ArticleDOI
Interleukin-18: Biological properties and role in disease pathogenesis
TL;DR: There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease, however,IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes also termed Macrophage Activation Syndrome.
Journal ArticleDOI
Macrophage activation syndrome in the era of biologic therapy.
TL;DR: The pathophysiology of MAS remains elusive, but observations in animal models, as well as data on the effects of new anticytokine therapies on rates and clinical presentations of MAS in patients with systemic juvenile idiopathic arthritis (sJIA), provide clues to the understanding of this perplexing clinical phenomenon.
Journal ArticleDOI
Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine- Directed Therapies
Grant S. Schulert,Alexei A. Grom +1 more
TL;DR: Clinically and pathologically, Macrophage activation syndrome bears strong similarity to hemophagocytic lymphohistiocytosis (HLH), and some authors prefer the term secondary HLH to describe it.
Journal ArticleDOI
Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era.
TL;DR: The authors are approaching the beginning of a new era of precision medicine for cytokine storm, in which understanding of the immunologic derangement of each individual trigger, and perhaps in each individual patient, will inform the choice of intervention.
References
More filters
Journal ArticleDOI
HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.
Jan-Inge Henter,AnnaCarin Horne,Maurizio Aricò,R. Maarten Egeler,Alexandra H. Filipovich,Shinsaku Imashuku,Stephan Ladisch,Kenneth L. McClain,David Webb,Jacek Winiarski,Gritta Janka +10 more
TL;DR: HLH‐2004 chemo‐immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids, and subsequent hematopoietic stem cell transplantation is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease.
Journal ArticleDOI
Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice
David Kägi,Birgit Ledermann,Kurt Bürki,Peter Seiler,Bernhard Odermatt,Kristin J. Olsen,Eckhard R. Podack,Rolf M. Zinkernagel,Hans Hengartner +8 more
TL;DR: Perforin-deficient mice have been generated by homologous recombination to determine whether the effects of CDS+ cytolytic T cells and natural killer cells are mediated by pore formation involving perform, and perforin is therefore a key effector molecule for T-cell- and natural Killer- cell-mediated cy tolysis.
Journal ArticleDOI
Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis
Susan E. Stepp,Dufourcq-Lagelouse R,Françoise Le Deist,Françoise Le Deist,Sadhna Bhawan,Stéphanie Certain,Porunelloor A. Mathew,Jan-Inge Henter,Michael J. Bennett,Alain Fischer,Alain Fischer,Geneviève de Saint Basile,Vinay Kumar +12 more
TL;DR: In this paper, the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients.
Journal ArticleDOI
Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus.
Kwok-Yung Yuen,Paul K.S. Chan,Malik Peiris,D. N. C. Tsang,Tak-Lun Que,Kennedy F. Shortridge,P. T. Cheung,W. K. To,E. T. F. Ho,R. Sung,A. F. B. Cheng +10 more
TL;DR: Avian Influenza A H5N1 virus causes human influenza-like illness with a high rate of complications in adults admitted to hospital, and rapid H5-subtype-specific laboratory diagnosis can be made by RT-PCR applied directly to clinical specimens.
Journal ArticleDOI
Interleukin-18 Binding Protein: A Novel Modulator of the Th1 Cytokine Response
Daniela Novick,Soohyun Kim,Giamila Fantuzzi,Leonid L. Reznikov,Charles A. Dinarello,Menachem Rubinstein +5 more
TL;DR: Interleukin-18 binding protein functions as an inhibitor of the early Th1 cytokine response, suggesting that viral products may attenuate IL-18 and interfere with the cytotoxic T cell response.