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Blood, 1 August 2004, Vol. 104, No. 3, pp. 735-743.
Prepublished online as a Blood First Edition Paper on April 6, 2004; DOI 10.1182/blood-2003-10-3413.
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IMMUNOBIOLOGY
An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder
Michael B. Jordan,
David Hildeman,
John Kappler, and
Philippa Marrack
From the Integrated Department of Immunology and the Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO; Howard Hughes Medical Institute, Denver, CO; National Jewish Medical and Research Center, Denver, CO; the Cincinnati Children's Hospital and the Division of Immunobiology, University of Cincinnati, OH.
Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8+ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFN ) is uniquely essential as well. Finally, the excessive amount of IFN seen in affected mice appears to be driven by increased antigen presentation to CD8+ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder.
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