Oral FTY720 administration induces immune tolerance and inhibits early development of atherosclerosis in apolipoprotein E-deficient mice.
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.
Department of Vascular and Thyroid Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
K
K
Huang
S Q
SQ
Li
W J
WJ
Wang
L S
LS
Liu
Y G
YG
Jiang
P N
PN
Feng
Y Q
YQ
Wang
S M
SM
Wang
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002791:Cholesterol, Dietary; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011409:Propylene Glycols / Q000008:administration & dosage*; D011498:Protein Precursors / Q000378:metabolism; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine