Statins Inhibit the Function of Human Antigen-Presenting Cells

Abstract Statins are lipid-lowering drugs that reduce cholesterol production by inhibition of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. It recently has been shown that statins, apart from their lipid-lowering action, have pleiotropic effects on the immune system. They possess immunomodulatory and anti-inflammatory activity. Our analysis of gene expression data comparing resting B cells with CD40-activated B cells, which are potent antigen-presenting cells (APC), showed that following CD40-activation expression of the enzymes in the mevalonate pathway was up-regulated. These results together with the known ability of some statins to directly interfere with the interaction of lymphocyte function-associated antigen 1 (LFA-1), an adhesion molecule involved in activation of APCs, with its ligands provided the rational for our investigation of the effects of HMG-CoA reductase inhibition on the function of human APCs. Addition of simvastatin led to inhibition of the proliferation and adhesion of B cells activated by via CD40 or TLR9. Likewise, the expression of MHC class II (HLA-DR) and of the costimulatory molecules CD80 and CD86 was reduced. The antigen presenting capacity of simvastatin-treated B cells was reduced as was shown by a reduction of T cell proliferation induced by allogeneic simvastatin-treated B cells. Simvastatin inhibited activation of resting B cells as well as already activated B cells. The inhibition was dose-dependent and doses as low as 10nM Simvastatin led to signification reduction of B cell activation. We observed similar effects on human dendritic cells. Interestingly, the concentration of simvastatin required for inhibition of T cell proliferation in response to stimulation by CD3/CD28-coated beads was 1–2 logs higher than for B cells. The inhibitory action of statins was only partially dependent on the mevalonate pathway since addition of excess mevalonate did not fully restore B cell activation. Our findings of the effects of statins on human APCs in conjunction with the observation made by others that preemptive treatment with a HMG-CoA reductase inhibitor protected mice from graft-versus-host-disease (GVHD) without affecting the graft-versus-leukemia effect provide the rational for further testing of statins in patients undergoing allogeneic stem cell transplantion. Since APCs are required for the development of acute GVHD the modulation of antigen presentation by DCs and B cells might be an important mechanism of action of statins. The exquisite sensitivity of APCs to statin-mediated inhibition could synergize with the T cell-directed immunosuppression of conventional immunosuppressants. In summary, statins represent a promising new immunomodulatory drug for the treatment immune-mediated diseases such as GVHD and autoimmune disease.