title: Au-ACRAMTU-PEt3 Alters Redox Balance To Inhibit T Cell Proliferation and Function.
abstract: Although T cells play a critical role in protection from viruses, bacteria, and tumors, they also cause autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Unwanted T cell responses during organ transplant, graft-versus-host disease, and allergies are also major clinical problems. Although drugs are available to suppress unwanted immune responses, they have limited efficacy with serious side effects. Thus, new therapeutics limiting T cell activation, proliferation, and function can make an immediate clinical impact. To identify new suppressors of lymphocyte activation, proliferation, and function, we examined the immunosuppressive activity of gold(I) analogs of platinum-acridine antitumor agents. We found that the gold complex Au-ACRAMTU-PEt3 is a potent suppressor of murine and human T cell activation. Preincubation with Au-ACRAMTU-PEt3 suppresses the proliferation of CD4(+) and CD8(+) T cells at a similar concentration as pharmaceutical grade cyclosporine A. Au-ACRAMTU-PEt3 pretreatment decreases the production of IFN-γ, TNF-α, IL-2, and IL-17 by human and murine CD4(+) and CD8(+) T cells. When mice were treated with Au-ACRAMTU-PEt3 during viral infection, the expansion of virus-specific CD8(+) T cells was decreased 10-fold and viral load was elevated. Taken together, these results demonstrate that Au-ACRAMTU-PEt3 has potent immunosuppressive activity that could be used to suppress immune responses during transplantation and autoimmunity.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27101;
authors.forename: P Kent
authors.initials: PK
authors.lastname: Langston
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109; and.
authors.forename: Mu
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109; and.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bierbach
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27101.
authors.forename: Derek
authors.initials: D
authors.lastname: Parsonage
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27101.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Poole
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27101;
authors.forename: Madeline J
authors.initials: MJ
authors.lastname: Price
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27101; jgrayson@wakehealth.edu.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Grayson
mesh_terms: D000166:Acridines / Q000737:chemistry; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008810:Mice, Inbred C57BL; D050607:Organogold Compounds / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010984:Platinum / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry; D019562:Viral Load / Q000187:drug effects / Q000276:immunology
chemical_list: C471910:1-(2-(acridin-9-ylamino)ethyl)-1,3-dimethylthiourea; D000166:Acridines; D016207:Cytokines; D050607:Organogold Compounds; D010984:Platinum; D014508:Urea; D002118:Calcium