24th annual meeting of the Histiocyte society, Berlin, Germany October 1–3, 2008

[[abstract]]Hemophagocytic syndrome (HPS) or hemopahgocytic lymphohistiocytosis (HLH) is afatal complication associated with severe viral infections, genetic disorders, ormalignancies. The pathogenesis of HPS is presumed to result from an enhancedproinammatory cytokine secretion and systemic macrophage activation, resulting insystemic organ damages. In the past years, our group worked on the pathogenesis ofHPS and claried that NFkB-mediated T cell and macrophage activation is the majormechanism. Therapy targeted at the pathogenic signaling pathways of HPS usingdrugs having minimal side effects is desirable. Since peroxisome proliferatorsactivated receptor (PPAR) agonists, regulators of cholesterol metabolism, have beenshown to exhibit profound effects on the inhibition of proinammatory cytokines andmacrophage activation through NFkB or AP-I pathway, rosiglitazone, a PPAR-gammaagonist, was tested for treatment of HPS using a rabbit model of Herpesvirus papio(HVP, an EBV homologue)-associated HPS. In vitro, rosiglitazone was shown toinhibit macrophage activation and secretion of tumor necrosis factor-alpha throughinhibition of NFkB signaling in the U937 cell line. Different doses of rosiglitazonewere fed to rabbits after intravenous injection of 5 107 copies of HVP virus atdifferent time courses (7 and 20 days, respectively) of infection. As compared to thecontrol group which succumbed consistently at around one month, the 4 mgrosiglitazone-treated group showed signicant improvement of survival when fed atan early stage (7 days) of infection (p < 0.01), while a higher dosage (8 mg) is neededto achieve therapeutic effect at advanced stage (20 days) of diseases (p < 0.05). Theviral load, TNF-alpha cytokine levels, and laboratory parameters also showedsignicant improvement in the rosiglitazone-treated group. PPAR agonists appear tobe active within model and should be considered for further clinical testing