Lovastatin Inhibits T-cell Proliferation While Preserving the Cytolytic Function of EBV, CMV, and MART-1-specific CTLs

Abstract

Statin treatment has been shown to reduce graft-versus-host disease (GVHD) while preserving graft-versus-tumor (GVT) effect in allogeneic stem cell transplantation (allo-HCT). Herein, we investigated whether lovastatin treatment affects the function of human cytolytic T lymphocytes (CTLs). Upon TCR stimulation, lovastatin significantly inhibited the proliferation of both CD4+ and CD8+ T cells from healthy donors while their intracellular cytokine production including IFN-γ and TNF-α remained the same with a slight decrease of IL-2. Moreover, the specific lysis of target cells by CTL lines derived from patients and normal donors specific for EBV-encoded antigen LMP2 or CMV-encoded antigen pp65 was uncompromised in the presence of lovastatin. In addition, we evaluated the effect of lovastatin on the proliferation and effector function of the CD8+ tumor–infiltrating lymphocytes (TILs) derived from melanoma patients specific for MART-1 antigen. Lovastatin significantly reduced the expansion of antigen-specific TILs upon MART-1 stimulation. However, the effector function of TILs, including the specific lysis of target cells and secretion of cytokine IFN-γ, remained intact with lovastatin treatment. Taken together, these data demonstrated that lovastatin inhibits the proliferation of EBV-, CMV- and MART-1-specific CTLs without affecting cytolytic capacity. The differential effect of lovastatin on the proliferation versus cytoxicity of CTLs might shed some light on elucidating the possible mechanisms of GVHD and GVT effect elicited by alloimmune responses.

Impact of rosuvastatin treatment on reduction of thrombus burden in rat acute inferior vena cava stenosis

“…Consistently, the number of these inflammatory and immune response cells was remarkably reduced in DVT animals after rosuvastatin treatment. Our findings are consistent with those of previous studies [23,24].…”

“…Therefore, statin has been suggested to shed some light on the pathogenesis of immunosuppressive graftversus-host disease [23,24]. An essential finding in the present study is that the number of immune response cells (CD3+/CD4+ helper T cells, CD3+/CD8+ cytotoxic T cells and CD4 + CD25 + Foxp3+ Tregs) were markedly increased in DVT animals compared with that in SC animals by days 2, 6 and 14 after IVC-stenosis procedure.…”

“…Interestingly, statin treatment has been shown to reduce the activity, differentiation and proliferation of cytotoxic T lymphocytes and the severity of graft-versus-host disease [23,24]. Therefore, statin has been suggested to shed some light on the pathogenesis of immunosuppressive graftversus-host disease [23,24].…”

Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1

“…Drugs such as lovastatin have been used to lower cell cholesterol levels in virus-infected cells (39)(40)(41) by affecting intermediate steps in the cholesterol-biosynthetic pathway but function only after several hours. The HSV-1 replicative cycle is complete within 18 to 24 h, and the rapid action of M␤CD in reducing cell cholesterol was better suited to this study.…”

Immunohistochemical and histomorphological analysis of rat mammary tumors after simvastatin treatment

“…Zhang et al [8] have observed that fluvastatin inhibited proliferation of hepatocellular carcinoma cell lines (HepG2, SMMC-7721 and MHCC-97H) by inducing apoptosis and G2/M phase arrest in a dose-dependent manner. In another experiment, acquired data demonstrated that lovastatin inhibits the proliferation of MART-1-specific human cytolytic T lymphocytes without affecting cytolytic capacity [19]. In the study of Bessler et al [20] malignant cell lines -HuCC, EHEB, K562, and Raji were incubated with three lipophilic statins (atorvastatin, lovastatin, and simvastatin) and one hydrophilic statin (pravastatin).…”