Immunotherapy With Tolerogenic Apolipoprotein B-100―Loaded Dendritic Cells Attenuates Atherosclerosis in Hypercholesterolemic Mice

• Published in: Circulation (New York, N.Y.) Vol. 123; no. 10; pp. 1083 - 1091
• Main Authors: HERMANSSON, Andreas, JOHANSSON, Daniel K, KETELHUTH, Daniel F. J, ANDERSSON, John, XINGHUA ZHOU, HANSSON, Göran K
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 15.03.2011
• Subjects: Animals; Aorta - immunology; Aorta - pathology; Apolipoprotein B-100 - therapeutic use; Atherosclerosis - immunology; Atherosclerosis - therapy; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; CD4-Positive T-Lymphocytes - immunology; Chronic Disease; Dendritic Cells - immunology; Dendritic Cells - transplantation; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Humans; Hypercholesterolemia - immunology; Hypercholesterolemia - therapy; Immunotherapy - methods; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin-10 - therapeutic use; Lymphocyte Activation - immunology; Male; MEDICAL AND HEALTH SCIENCES; Medical sciences; MEDICIN OCH HÄLSOVETENSKAP; Mice; Spleen - immunology; Th1 Cells - immunology; Th2 Cells - immunology; Vertebrates: cardiovascular system; Lipids; Cardiovascular disease; Hyperlipoproteinemia; Lipoprotein; Vascular disease; Apolipoprotein B; Immunology; Immunotherapy; Atherosclerosis; cytokines; β Cell; Dyslipemia; lipoproteins; Dendritic cell; apolipoproteins; Rodentia; Cytokine; Metabolic diseases; Inflammation; Cholesterol; Vertebrata; Mammalia; Hypercholesterolemia; Treatment; Mouse; Animal
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.110.973222

Atherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic vascular inflammation with an autoimmune response to low-density lipoprotein components. To dampen the inflammatory component of atherosclerosis, we injected hypercholesterolemic huB100(tg) × Ldlr(-/-) mice (mice transgenic for human apolipoprotein B100 [ApoB100] and deficient for the low-density lipoprotein receptor) intravenously with dendritic cells (DCs) that had been pulsed with the low-density lipoprotein protein ApoB100 in combination with the immunosuppressive cytokine interleukin-10. DCs treated with ApoB100 and interleukin-10 reduced proliferation of effector T cells, inhibited production of interferon-γ, and increased de novo generation of regulatory T cells in vitro. Spleen cells from mice treated with DCs plus ApoB100 plus interleukin-10 showed diminished proliferative responses to ApoB100 and significantly dampened T-helper 1 and 2 immunity to ApoB100. Spleen CD4(+) T cells from these mice suppressed activation of ApoB100-reactive T cells in a manner characteristic of regulatory T cells, and mRNA analysis of lymphoid organs showed induction of transcripts characteristic of these cells. Treatment of huB100(tg) × Ldlr(-/-) mice with ApoB100-pulsed tolerogenic DCs led to a significant (70%) reduction of atherosclerotic lesions in the aorta, with decreased CD4(+) T-cell infiltration and signs of reduced systemic inflammation. Tolerogenic DCs pulsed with ApoB100 reduced the autoimmune response against low-density lipoprotein and may represent a novel possibility for treatment or prevention of atherosclerosis.