Artesunate and a major metabolite, dihydroartemisinin, diminish mitogen-induced lymphocyte proliferation and...

Artemisinin derivatives are potent antimalarial compounds that may have immunomodulatory properties. Artesunate (range 0.01-2 mirog/ml) or dihydroartemisinin (range 0.01-8 microg/ml; DHART) were added to peripheral blood mononuclear cells (PBMC) or whole blood (WB) cultures before or simultaneously upon stimulation with phytohemagglutinin (PHA), a T cell mitogen. Lymphoproliferation was then measured by 3[H]-thymidine incorporation, and CD4+ and CD8+ T cell activation was assessed by expression of CD69 or CD25 using flow cytometry. Reverse transcriptase polymerase chain reaction depicted PBMC mRNA production for interleukins 2, 4, 12, and 15, interferon-gamma, and tumor necrosis factor-alpha. Artesunate concentrations between 0.1-1.5 microg/ml reduced lymphoproliferation in PHA-stimulated PBMC and WB cultures in a generally dose-dependent manner; inhibition by DHART was similar. Removing artesunate from PBMC before PHA was added abolished the reduction. PBMCs cultured with artesunate or DHART simultaneously with PHA showed modestly reduced proportions of CD4+ and CD8+ T cells expressing CD69 and CD25. Artesunate had little effect on qualitative cytokine mRNA levels in PHA-stimulated PBMC cultures. Artesunate and DHART may diminish some PBMC responses to immunologic stimuli. Further work is warranted to define the mechanisms involved, and whether this affects malaria treatment.