title: Ras inhibition increases the frequency and function of regulatory T cells and attenuates type-1 diabetes in non-obese diabetic mice.
abstract: Regulatory T cells (Treg) reportedly suppress diabetes in non-obese diabetic (NOD) mice, and the frequency and functional suppressive properties of Treg were found to be upregulated by inhibition of Ras. We thus postulated that treatment with the Ras inhibitor 5-fluoro-farnesylthiosalicylic acid (F-FTS), a derivative of S-farnesylthiosalicylic acid (FTS), would attenuate diabetes development in NOD mice. To test this hypothesis we assayed Foxp3, total Ras, and GTP-Ras in NOD splenocytes following their exposure to FTS and F-FTS in vitro. In splenocytes exposed to FTS, and even more so to F-FTS, Foxp3 expression was increased and GTP-Ras expression reduced. We also injected NOD mice intraperitoneally with F-FTS and assessed both their Treg pools and the occurrence of diabetes. The treated mice showed a significant increase in the frequency of spleen-cell-derived Foxp3+ Treg, and their Treg were more effective than Treg from untreated NOD controls in suppressing the proliferation of effector T cells. Moreover, the F-FTS treatment also attenuated the development of diabetes in the NOD mice. The mice were then killed and their insulin and cytokine levels assayed. The treated mice showed an increase in circulating insulin but no change in cytokine concentrations. One of the mechanisms underlying our novel finding that treatment with a Ras inhibitor ameliorates the development of experimental type-1 diabetes could thus conceivably be an augmentation in the frequency and functional suppressive properties of Treg. Ras inhibition might therefore be worth developing as a new treatment modality in patients with type 1 diabetes.
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Mor
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.forename: Gad
authors.initials: G
authors.lastname: Keren
authors.forename: Jacob
authors.initials: J
authors.lastname: George
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors*; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D016283:Proto-Oncogene Proteins p21(ras)