Abstract
Orally administered immunomodulatory drugs have recently demonstrated the ability to induce an oral tolerance via inhibition of effector T cells and induction of certain subsets of regulatory T cells (Tregs) which have the potential to prevent several autoimmune diseases. In the present study, we hypothesized that short-term, low-dose, oral FTY720 administration may induce latency-associated peptide (LAP) Tregs and CD4(+) Foxp3(+) Tregs in atherogenesis, potentially resulting in remission of early development of atherosclerosis in apolipoprotein E-deficient (APOE(-/-)) mice. FTY720 was orally administered to APOE(-/-) mice 4 weeks of age on a high-cholesterol diet and atherosclerosis was assessed at 8 weeks of age. Oral administration of FTY720 significantly reduced atherosclerotic lesion formation compared with control mice. We observed a significant increase in LAP(+) and Foxp3(+) cells in the CD4+T-cell population of FTY720-treated mice in association with increased production of the anti-inflammatory cytokine transforming growth factor-β (TGF-β) as well as suppressed T-helper type 1 immune responses. Our findings reveal that short-term, low-dose oral FTY720 treatment had great benefits in inhibiting early development of atherosclerosis in mice via induction of a regulatory T-cell response and inhibition of effector T responses. These findings suggest that oral immune modulation may represent an attractive therapeutic approach to atherosclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Aorta / drug effects*
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Aorta / immunology
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Aorta / metabolism
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Aorta / pathology
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Aortic Diseases / genetics
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Aortic Diseases / immunology
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Aortic Diseases / metabolism
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Aortic Diseases / pathology
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Aortic Diseases / prevention & control*
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Apolipoproteins E / deficiency*
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Apolipoproteins E / genetics
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Atherosclerosis / genetics
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Atherosclerosis / immunology
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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Atherosclerosis / prevention & control*
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Cell Proliferation / drug effects
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Cells, Cultured
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Cholesterol, Dietary
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Cytokines / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Fingolimod Hydrochloride
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Forkhead Transcription Factors / metabolism
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Immune Tolerance / drug effects*
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Immunosuppressive Agents / administration & dosage*
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Lymphocyte Activation / drug effects
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Male
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Mice
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Mice, Knockout
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Propylene Glycols / administration & dosage*
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Protein Precursors / metabolism
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Sphingosine / administration & dosage
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Sphingosine / analogs & derivatives*
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Time Factors
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Transforming Growth Factor beta / metabolism
Substances
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Apolipoproteins E
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Cholesterol, Dietary
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Cytokines
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Immunosuppressive Agents
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Propylene Glycols
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Protein Precursors
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Transforming Growth Factor beta
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Fingolimod Hydrochloride
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Sphingosine