1. Au-ACRAMTU-PEt3 Alters Redox Balance To Inhibit T Cell Proliferation and Function.
- Author
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Langston PK, Yang M, Bierbach U, Parsonage D, Poole LB, Price MJ, and Grayson JM
- Subjects
- Acridines chemistry, Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Calcium metabolism, Cells, Cultured, Cytokines immunology, Cytokines metabolism, Dose-Response Relationship, Drug, Female, Flow Cytometry, Humans, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Lymphocytic Choriomeningitis drug therapy, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus drug effects, Lymphocytic choriomeningitis virus immunology, Lymphocytic choriomeningitis virus physiology, Mice, Inbred C57BL, Organogold Compounds chemistry, Oxidation-Reduction drug effects, Platinum chemistry, Urea analogs & derivatives, Urea chemistry, Viral Load drug effects, Viral Load immunology, CD4-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes drug effects, Organogold Compounds pharmacology
- 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., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
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