Immunotherapy With Tolerogenic Apolipoprotein B-100―Loaded Dendritic Cells Attenuates Atherosclerosis in Hypercholesterolemic Mice
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 inje...
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| Published in: | Circulation (New York, N.Y.) Vol. 123; no. 10; pp. 1083 - 1091 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
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Hagerstown, MD
Lippincott Williams & Wilkins
15-03-2011
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| Abstract | 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. |
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| AbstractList | BACKGROUNDAtherosclerosis 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.METHODS AND RESULTSTo 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.CONCLUSIONSTolerogenic DCs pulsed with ApoB100 reduced the autoimmune response against low-density lipoprotein and may represent a novel possibility for treatment or prevention of atherosclerosis. BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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. 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. |
| Author | ANDERSSON, John KETELHUTH, Daniel F. J XINGHUA ZHOU HERMANSSON, Andreas JOHANSSON, Daniel K HANSSON, Göran K |
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| Keywords | 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 |
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| Snippet | Atherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic vascular... BACKGROUNDAtherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic... BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic... |
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| SubjectTerms | 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 |
| Title | Immunotherapy With Tolerogenic Apolipoprotein B-100―Loaded Dendritic Cells Attenuates Atherosclerosis in Hypercholesterolemic Mice |
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