Testing Different Therapeutics on Mouse Model of Hemophagocytic Lymphohistiocytosis in Particular in Combination with IFN-? Blockade

Abstract

By Minh Tran, Medical Sciences

Advisor: Michael Jordan

Presentation ID: PM_D37

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease, in which the immune cells especially T cells become hyperactive, causing inflammation and damaging the body's own tissues and organs. To study this disease, our lab has developed a mouse model of HLH. Perforin knockout (Prf-/-) mouse after being infected with lymphocytic choriomeningitis virus (LCMV) recapitulates the clinical manifestation of HLH patient. Although current treatment for HLH patients includes neutralizing IFN-? cytokine, 20% of patients do not respond well to INF-? blockade. Clinical testing trials and gene expression study in HLH mouse model suggested that CD8 T cell activation is essential for the pathology development upon IFN-? blockade. Our hypothesis is that in complementation with IFN-? blockade, agents interfering with CD8 T cell activation, specifically Abatacept and Rapamycin, are potential therapeutics for treating HLH. To test their therapeutics' effect, we treated either Abatacept or Rapamycin in combination with anti IFN-? for HLH mice model and monitored their survival, weight loss, and clinical score for 40 days. To assess how well T cell activation is suppressed, we also did a short-term therapy experiment where splenocytes from mice treated with therapeutics were isolated on day 16, stained, and analyzed for the expression of T cell activation markers. In combination with IFN-? blockade, Abatacept improved the mice's well-being and efficiently suppressed T cells activation while Rapamycin exerted a subtle effect on T cells suppression. Future studies could use a potential combination therapy consisting of Abatacept, Rapamycin, and IFN-? blockade to prevent the pathology development of HLH.