Attenuation of early atherosclerotic lesions by immunotolerance with β2 glycoprotein I and the immunomodulatory effectors interleukin 2 and 10 in a murine model

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Abstract

Objective:

This study assessed the effect of cellular and humoral autoimmune response inhibition after immunization with β2-glycoprotein I (β2-GPI) and the effect of immunomodulation with interleukin (IL)-2 and IL-10 in the development of early atherosclerotic vascular lesion in a murine model. Atherosclerosis is increasingly considered a chronic inflammatory disease with pathogenic autoimmune processes. Regulatory T cells, and their cytokines, have been implicated in the inhibition of the development of atherosclerotic lesions and involved in the immunologic tolerance induction.

Methods:

Eight-week-old male C57BL6 LDL-receptor deficient (LDLR−/−) mice were fed a cholesterol-rich (2.8%), high-saturated-fat (82%) diet for a week and divided in five groups. The groups received the following intravenous immunizations: group I (control group): one dose of 5 μg β2-GPI; group II: 5 μg β2-GPI I and 1 μg IL-2; group III: 5 μg β2-GPI and 0.75 μg of IL-10; and group IV: 5 μg β2-GPI, 1 μg IL-2, and 0.75 μg IL-10. The aortas of the mice were assessed 8 weeks after inoculation to determine the aortic lesion size and composition in all groups.

Results:

β2-GPI immunization attenuated the early atherosclerotic lesions development compared with the control group (P= .001). Macroscopic and histologic aortic atherosclerotic lesions were significantly decreased in the IL-2 and IL-10-treated groups in β2-GPI-tolerant mice compared with the β2-GPI-tolerant group without cytokine injection (P= .001). The association of both cytokines did not provoke a major inhibition in the atherosclerosis development when compared with groups injected with the two cytokines separately.

Conclusions:

The immunotolerance induction against β2-GPI attenuates the development of atherosclerosis lesions in an animal model, enhanced by downregulation of the cellular and humoral autoimmune response provoked by IL-2 and IL-10.

Clinical Relevance:

This report shows the effect of cellular autoimmune response inhibition after immunization with β2-glycoprotein I and the effect of immunomodulation with interleukin (IL)-2 and IL-10 in the development of early atherosclerotic vascular lesion in a murine model, concluding that the immunotolerance induction against β2-glycoprotein I attenuates the development of atherosclerosis through downregulation of cellular autoimmune response provoked by IL-2 and IL-10. The novel results drawn from this preclinical in vivo study provide substantial information regarding atherosclerosis pathogeny and a potential clinical application in the near future.

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