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

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.

• Authors: Roland Klingenberg, Michael Lebens, Andreas Hermansson, Gunilla Nordin Fredrikson, Daniela Strodthoff, Mats Rudling, Daniel F J Ketelhuth, Norbert Gerdes, Jan Holmgren, Jan Nilsson, Göran K Hansson
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 5 Pg. 946-52 (May 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20167655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Administration, Intranasal
• Aerosols
• Animals
• Aortic Diseases (genetics, immunology, metabolism, pathology, prevention & control)
• Apolipoprotein B-100 (administration & dosage, immunology)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (genetics, immunology, metabolism, pathology, prevention & control)
• Cholera Toxin (administration & dosage, 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, immunology)
• Interleukin-10 (genetics)
• Mice
• Mice, Knockout
• Nasal Mucosa (drug effects, immunology)
• Ovalbumin (administration & dosage, immunology)
• Peptide Fragments (administration & dosage, 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, immunology)
• Vaccines, Synthetic (administration & dosage, immunology)