Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice.
OBJECTIVE
The immunoinflammatory response plays a critical role in the development and progression of atherosclerosis. Recent studies suggested an important role for regulatory T (Treg) cells in the inhibition of disease-related vascular inflammation. We hypothesized that induction of a specific Treg cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance.


RESULTS
Young or old Apoe-/- mice were subcutaneously infused for 2 weeks with either a control ovalbumin (OVA) peptide or with apolipoprotein B100 (ApoB100)-derived peptides without adjuvant. Atherosclerosis development, progression and immunologic status were assessed at 8 weeks after the end of the infusion. Treatment with ApoB100 peptides led to significant reduction of lesion development in young Apoe-/- mice (P=0.001 versus OVA group) and abrogated atherosclerosis progression in old Apoe-/- mice with already established lesions (0% progression in ApoB100 versus 17% in OVA group, P<0.005). Limitation of plaque progression was associated with reduced vascular inflammation and increased collagen content, indicative of plaque stabilization. Infusion of ApoB100 peptides did not alterantibody production but promoted a specific Treg cell response, which was associated with a reduction of both T helper type 1-related and T helper type 2-related cytokines. Interestingly, depletion of CD4+CD25+ Treg cells abrogated ApoB100 peptides-dependent immune modulation and atheroprotection.


CONCLUSIONS
Subcutaneous infusion of adjuvant-free ApoB100-derived peptides to Apoe-/- mice reduces atherosclerosis through the induction of a specific Treg cell response.
Institut National de la Santé et de la Recherche Médicale, Unit 970, Paris Cardiovascular Research Center, Paris, France.
Olivier
O
Herbin
Hafid
H
Ait-Oufella
Wang
W
Yu
Gunilla Nordin
GN
Fredrikson
Benjamin
B
Aubier
Nicolas
N
Perez
Véronique
V
Barateau
Jan
J
Nilsson
Alain
A
Tedgui
Ziad
Z
Mallat
D000818:Animals; D053299:Apolipoprotein B-100 / Q000008:administration & dosage*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D055104:Infusions, Subcutaneous; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage; D010455:Peptides / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D053299:Apolipoprotein B-100; D001057:Apolipoproteins E; D016207:Cytokines; D010455:Peptides; D010047:Ovalbumin