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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2677.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

From the Division of Biopharmaceutics (G.H.M.v.P., T.v.E., E.J.A.v.W., K.L.L.H., P.d.V., T.J.C.v.B., J.K.), Leiden University, and the Department of Infectious Diseases and Immunology (R.v.d.Z., W.v.E.), Utrecht University, the Netherlands.

Correspondence to G.H.M. van Puijvelde, LACDR, Division of Biopharmaceutics, PO Box 9502, 2300 RA Leiden, The Netherlands. E-mail puijvelde{at}chem.leidenuniv.nl

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)-β by lymph node cells in response to HSP60 was observed after tolerance induction.

Conclusion— 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-β. 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.

HSP60-specific T cells contributing to the development of atherosclerosis can be counteracted by Tregs, which can be activated by oral tolerance induction to HSP60 and may produce IL-10 and TGF-β. This results in a beneficial effect on atherosclerosis and may provide a new therapeutic approach for the treatment of atherosclerosis.

Key Words: atherosclerosis • immune system • tolerance induction • regulatory T cells • heat shock proteins