Abstract
Background
In the course of atherosclerosis, humans and apolipoprotein (apoE) Knockout (KO) mice exhibit an active cell-mediated and humoral immune process, both at the systemic level and within atheromata. Low density lipoproteins (LDL) infiltrate the vascular wall, where they are oxidatively modified. This oxidative modification may generate new epitopes for which tolerance is not achieved during ontogenesis. Such epitopes could constitute new targets for autoreactive immune responses that may have a physiopathological role in disease development.
Materials and Methods
Exposing mice to high dose of antigens during thymic T-cell education induces immunological tolerance to the administered antigens. We injected newborn apoE KO mice with oxidized LDL. They were fed a cholesterol-rich diet and aortic atherosclerosis, cell-mediated immune response, and T-cell repertoire were analyzed after 5 months.
Results
Injection of oxidized LDL at birth reduced not only the immune response to oxidized LDL, but also susceptibility to atherosclerosis in apoE mice. Injection of oxidized LDL induced T-cell tolerance due to clonal deletion, rather than anergy of the reactive T cells. The T-cell repertoire of apoE KO mice was affected by the development of the disease, whereas tolerization normalized it.
Conclusions
This study demonstrates that the immune response against oxidized LDL has a deleterious role in atherogenesis and that a fine-tuning of this response could modify the course of the disease.
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Acknowledgment
We thank Ingrid Törnberg, Kerstin Carlson, Inger Bodin, and Anita Larsson for excellent technical assistance. This work was supported by the Swedish Medical Research Council (proj. 6816) and Heart-Lung Foundation, the Johnson and Wallenberg Foundations, King Gustaf V 80th Anniversary Fund, Tore Nilsson Foundation, and the AFA Research Fund, A. N. was the recipient of a Marie Curie postdoctoral research fellowship from the European Union.
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Nicoletti, A., Paulsson, G., Caligiuri, G. et al. Induction of Neonatal Tolerance to Oxidized Lipoprotein Reduces Atherosclerosis In ApoE Knockout Mice. Mol Med 6, 283–290 (2000). https://doi.org/10.1007/BF03401937
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DOI: https://doi.org/10.1007/BF03401937