Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis

Arterioscler Thromb Vasc Biol. 2010 May;30(5):946-52. doi: 10.1161/ATVBAHA.109.202671. Epub 2010 Feb 18.

Abstract

Objective: Atherosclerosis is an inflammatory disease. Autoimmune responses to low-density lipoproteins (LDL) contribute to its progression, whereas immunization with LDL may induce atheroprotective or proatherogenic responses. The objective of this study was to develop an atheroprotective vaccine by targeting a peptide of the LDL protein constituent apolipoprotein B-100 (apoB-100) to the nasal mucosa to induce a protective mucosal immune response.

Methods and results: A peptide comprising amino acids 3136 to 3155 of apoB-100 (p210) was fused to the B subunit of cholera toxin (CTB), which binds to a ganglioside on mucosal epithelia. The effect of nasal administration of the p210-CTB fusion protein on atherogenesis was compared with that of an ovalbumin peptide fused to CTB and with untreated controls. Immunization with p210-CTB for 12 weeks caused a 35% reduction in aortic lesion size in Apoe(-/-) mice. This effect was accompanied by induction of regulatory T cells that markedly suppressed effector T cells rechallenged with apoB-100 and increased numbers of interleukin (IL)-10(+) CD4(+) T cells. Furthermore, a peptide-specific antibody response was observed. Atheroprotection was also documented in apoe(-/-) mice lacking functional transforming growth factor-beta receptors on T cells.

Conclusion: Nasal administration of an apoB-100 peptide fused to CTB attenuates atherosclerosis and induces regulatory Tr1 cells that inhibit T effector responses to apoB-100.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Aerosols
  • Animals
  • Aortic Diseases / genetics
  • Aortic Diseases / immunology
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Apolipoprotein B-100 / administration & dosage*
  • Apolipoprotein B-100 / immunology
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Cholera Toxin / administration & dosage*
  • Cholera Toxin / immunology
  • Disease Models, Animal
  • Female
  • Forkhead Transcription Factors / genetics
  • Humans
  • Immunity, Cellular / drug effects
  • Immunity, Humoral / drug effects
  • Immunity, Mucosal / drug effects
  • Immunoconjugates / administration & dosage*
  • Immunoconjugates / immunology
  • Interleukin-10 / genetics
  • Mice
  • Mice, Knockout
  • Nasal Mucosa / drug effects
  • Nasal Mucosa / immunology
  • Ovalbumin / administration & dosage
  • Ovalbumin / immunology
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / immunology
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Messenger / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Vaccines, Synthetic / administration & dosage*
  • Vaccines, Synthetic / immunology

Substances

  • Aerosols
  • Apolipoprotein B-100
  • Apolipoproteins E
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Immunoconjugates
  • Peptide Fragments
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Vaccines, Synthetic
  • Interleukin-10
  • Ovalbumin
  • Cholera Toxin
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II