Lovastatin inhibits T-cell proliferation while preserving the cytolytic function of EBV, CMV, and MART-1-specific CTLs.
Statin treatment has been shown to reduce graft-versus-host disease while preserving graft-versus-tumor effect in allogeneic stem cell transplantation. Herein, we investigated whether lovastatin treatment affects the function of human cytolytic T lymphocytes (CTLs). Upon T-cell receptor stimulation, lovastatin significantly inhibited the proliferation of both CD4+ and CD8+ T cells from healthy donors whereas their intracellular cytokine production including interferon-γ and tumor necrosis factor-α remained the same with a slight decrease of interleukin-2. Moreover, the specific lysis of target cells by CTL lines derived from patients and normal donors specific for Epstein-Barr virus-encoded antigen latent membrane protein-2 or cytomegalovirus-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 interferon-γ, remained intact with lovastatin treatment. Taken together, these data demonstrated that lovastatin inhibits the proliferation of Epstein-Barr virus, cytomegalovirus, and MART-1-specific CTLs without affecting cytolytic capacity. The differential effect of lovastatin on the proliferation versus cytotoxicity of CTLs might shed some light on elucidating the possible mechanisms of graft-versus-host disease and graft-versus-tumor effect elicited by alloimmune responses.
Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Dan
D
Li
Yufeng
Y
Li
Jessica A
JA
Hernandez
Rebecca
R
Patenia
Tae Kon
TK
Kim
Jahan
J
Khalili
Mark C
MC
Dougherty
Patrick J
PJ
Hanley
Catherine M
CM
Bollard
Krishna V
KV
Komanduri
Patrick
P
Hwu
Richard E
RE
Champlin
Laszlo G
LG
Radvanyi
Jeffrey J
JJ
Molldrem
Qing
Q
Ma
D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003587:Cytomegalovirus / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000473:pathology; D058965:MART-1 Antigen / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010750:Phosphoproteins / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014763:Viral Matrix Proteins / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D058965:MART-1 Antigen; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D008148:Lovastatin