Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis

G H M van Puijvelde; T van Es; E J A van Wanrooij; K L L Habets; P de Vos; R van der Zee; W van Eden; Th J C van Berkel; J Kuiper

doi:10.1161/ATVBAHA.107.151274

Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis

Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2677-83. doi: 10.1161/ATVBAHA.107.151274. Epub 2007 Sep 27.

Authors

G H M van Puijvelde¹, T van Es, E J A van Wanrooij, K L L Habets, P de Vos, R van der Zee, W van Eden, Th J C van Berkel, J Kuiper

Affiliation

¹ LACDR, Division of Biopharmaceutics, PO Box 9502, 2300 RA Leiden, The Netherlands. [email protected]

PMID: 17901374
DOI: 10.1161/ATVBAHA.107.151274

Abstract

Objective: HSP60-specific T cells contribute to the development of the immune responses in atherosclerosis. This can be dampened by regulatory T cells activated via oral tolerance induction, and we explored the effect of oral tolerance induction to HSP60 and the peptide HSP60 (253 to 268) on atherosclerosis.

Methods and results: HSP60 and HSP60 (253 to 268) were administered orally to LDLr(-/-) mice before induction of atherosclerosis and resulted in a significant 80% reduction in plaque size in the carotid arteries and in a 27% reduction in plaque size at the aortic root. Reduction in plaque size correlated with an increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells in several organs and in an increased expression of Foxp3, CD25, and CTLA-4 in atherosclerotic lesions of HSP60-treated mice. The production of interleukin (IL)-10 and transforming growth factor (TGF)-beta by lymph node cells in response to HSP60 was observed after tolerance induction.

Conclusions: Oral tolerance induction to HSP60 and a small HSP60-peptide leads to an increase in the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells, resulting in a decrease in plaque size as a consequence of increased production of IL-10 and TGF-beta. We conclude that these beneficial results of oral tolerance induction to HSP60 and HSP60 (253 to 268) may provide new therapeutic approaches for the treatment of atherosclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antibodies / blood
Antigens, CD / metabolism
Antigens, Differentiation / metabolism
Atherosclerosis / genetics
Atherosclerosis / immunology
Atherosclerosis / metabolism
Atherosclerosis / pathology
Atherosclerosis / prevention & control*
CTLA-4 Antigen
Carotid Arteries / immunology
Carotid Arteries / metabolism
Carotid Arteries / pathology
Cell Proliferation
Cells, Cultured
Chaperonin 60 / administration & dosage
Chaperonin 60 / immunology*
Dietary Fats / administration & dosage
Disease Models, Animal
Dose-Response Relationship, Immunologic
Epitopes, T-Lymphocyte
Forkhead Transcription Factors / metabolism
Immune Tolerance*
Immunotherapy / methods*
Interleukin-10 / metabolism
Interleukin-2 Receptor alpha Subunit / metabolism
Mice
Mice, Knockout
Peptide Fragments / administration & dosage
Peptide Fragments / immunology*
RNA, Messenger / metabolism
Receptors, LDL / deficiency
Receptors, LDL / genetics
Receptors, LDL / metabolism*
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Transforming Growth Factor beta / metabolism

Substances

Antibodies
Antigens, CD
Antigens, Differentiation
CTLA-4 Antigen
Chaperonin 60
Ctla4 protein, mouse
Dietary Fats
Epitopes, T-Lymphocyte
Forkhead Transcription Factors
Foxp3 protein, mouse
Interleukin-2 Receptor alpha Subunit
Peptide Fragments
RNA, Messenger
Receptors, LDL
Transforming Growth Factor beta
Interleukin-10