The orally available, synthetic ether lipid edelfosine inhibits T cell proliferation and induces a type I interferon response

• Published in: PloS one Vol. 9; no. 3; p. e91970
• Main Authors: Abramowski, Pierre, Otto, Benjamin, Martin, Roland
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.03.2014; Public Library of Science (PLoS)
• Subjects: Analysis; Antineoplastic Agents - pharmacology; Apoptosis; Autoimmune diseases; Autoimmunity; Biological response modifiers; Biology and Life Sciences; Biomarkers - metabolism; Brain research; Cancer therapies; Care and treatment; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Cell death; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Cytokines - genetics; Cytokines - metabolism; Cytotoxicity; Disease; Drug dosages; Enzyme-Linked Immunosorbent Assay; Experimental allergic encephalomyelitis; Flow Cytometry; Gene expression; Gene Expression Profiling; Genes; Genomes; Haplotypes; Humans; Immune system; Immunoenzyme Techniques; Infections; Interferon; Interferon Type I - pharmacology; Internal medicine; Lecithin; Lipid rafts; Lipids; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Lysophosphatidylcholine; Major histocompatibility complex; Medical research; Medical treatment; Medicine and Health Sciences; Membranes; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Oligonucleotide Array Sequence Analysis; Phosphatidylcholine; Phospholipid Ethers - pharmacology; Rafts; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal transduction; T cells; Transcription; Transcription (Genetics); Viral infections; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0091970

The drug edelfosine is a synthetic analog of 2-lysophosphatidylcholine. Edelfosine is incorporated by highly proliferating cells, e.g. activated immune cells. It acts on cellular membranes by selectively aggregating the cell death receptor Fas in membrane rafts and interference with phosphatidylcholine (PC) synthesis with subsequent induction of apoptosis. Edelfosine has been proposed for the treatment of autoimmune diseases like multiple sclerosis (MS). Earlier studies on the animal model of MS, experimental autoimmune encephalomyelitis (EAE), have generated first evidence for the efficacy of edelfosine treatment. However, it is unknown if the previously described mechanisms for edelfosine action, which are derived from in vitro studies, are solely responsible for the amelioration of EAE or if edelfosine may exert additional effects, which may be beneficial in the context of autoimmunity. Since it was the purpose of our studies to assess the potential usefulness of edelfosine for the treatment of MS, we examined its mechanism/s of action on immune functions in human T cells. Low doses of edelfosine led to a decrease in homeostatic proliferation, and further studies of the mechanism/s of action by genome-wide transcriptional profiling showed that edelfosine reduces the expression of MHC class II molecules, of molecules involved in MHC class II-associated processing and presentation, and finally upregulated a series of type I interferon-associated genes. The inhibition of homeostatic proliferation, as well as the effects on MHC class II expression and -presentation, and the induction of type I interferon-associated genes are novel and interesting in the context of developing edelfosine for clinical use in MS and possibly also other T cell-mediated autoimmune diseases.