The Effects of the Repeated Administration of Resveratrol Monomer and Resveratrol Dimer on Circulating Immune Cells in Healthy Individuals

Background and aims: Resveratrol is a natural occurring polyphenol that has various health promoting properties including anti-inflammatory, anti-aging and heart protective effects, and it has also shown a promising anticancer potential (reviewed in Nature Reviews Drug Discovery, 2006). We recently reported that resveratrol may promote tumor immunosurveillance by inducing NKG2D ligands in tumor cells thereby sensitizing the transformed cells to NK cells killing (Cancer Science, 2013). Notably, despite the fact that resveratrol has been extensively studied in several in vitro and preclinical models, little is still known about its in vivo effects in humans. Based on preclinical data, we therefore initiated a phase I clinical trial to explore the safety of repeated doses of resveratrol in Japanese healthy volunteers and to also evaluate its effects on circulating immune cells.

Methods: In this study, we evaluated the cellular and molecular immune response in 14 healthy volunteers at baseline and after the oral administration of both resveratrol monomer at 1 Gr/day in seven individuals and resveratrol dimer, given to 7 subjects at 500 mg/day for 28 days. We obtained blood specimens at baseline, and then every 2 weeks for a total of 12 weeks. We assessed the plasma levels of 13 cytokines and chemokines by a luminex assay. In addition, we performed high-performance liquid chromatography-UV to measure resveratrol and its metabolites in both plasma and urine samples. We also evaluated the lymphocyte phenotypes by flow cytometry.

Results: The consumption of resveratrol monomer and resveratrol dimer did not cause any adverse events in the individuals evaluated in this study and the plasma levels of resveratrol and its metabolites could thus be accurately measured in both plasma and urine. Consistent with their reported antioxidant properties, the administration of resveratrol monomer (1.5 fold, p=0.01) or resveratrol dimer (2 fold p=0.01) resulted in a significant increase in the antioxidant activity of the plasma compared with the corresponding antioxidant baseline activity. The administration of resveratrol monomer, but not resveratrol dimer, resulted in an increase in the number of CD3- CD56+ and NKG2D+ circulating lymphocytes (p=0.05). Conversely, the circulating numbers of monocytes, B and T lymphocytes remained essentially unchanged throughout the course of the study. Phenotypic studies revealed a significant increase in the expression level of NKG2D receptor on NK cells (p=0.01) and gamma delta T cells (p=0.05) in the individuals receiving either resveratrol dimer or monomer. The activator receptor DNAM-1 was also upregulated in the NK cells obtained from individuals receiving resveratrol. Other NK cells receptors including NKp46, NKp30 and NKG2A remained essentially unchanged. Protein profiling demonstrated significant increases in the circulating levels of immune-related cytokines including CXCL10 ( P=0.01), and MCP-1 (P=0.001), which became apparent by the second week after resveratrol administration. In contrast, the circulating levels of IL-6, IL-10, IL-15, VEGF, and ILR1a remained at baseline levels after resveratrol administration.

Conclusions: This is the first study to characterize the effects of resveratrol administration on human circulating immune cells in vivo, and these findings demonstrate that resveratrol clearly has some biological effects on immune cells.