An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder

(HLH) is a rare disorder with familial and acquired forms. The familial form is asso-ciated with mutations in the perforin gene and both forms are associated with se-vere defects in lymphocyte cytotoxic func-tion. 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 cho-riomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytope-nia, hypertriglyceridemia, hypofibrinogen-emia, 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 es-sential as well. Finally, the excessive amount of IFN seen in affected mice appears to be driven by increased anti-gen presentation to CD8 T cells. These studies provide insight into the patho-physiology of HLH, and provide new tar-gets for specific therapeutic intervention in this fatal disorder. (Blood. 2004;104