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


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.


CONCLUSIONS
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.
Klingenberg
Roland
R
Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
Lebens
Michael
M
Hermansson
Andreas
A
Fredrikson
Gunilla Nordin
GN
Strodthoff
Daniela
D
Rudling
Mats
M
Ketelhuth
Daniel F J
DF
Gerdes
Norbert
N
Holmgren
Jan
J
Nilsson
Jan
J
Hansson
Göran K
GK
D000281:Administration, Intranasal; D000336:Aerosols; D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053299:Apolipoprotein B-100 / Q000008:administration & dosage* / Q000276:immunology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D018928:Immunity, Mucosal / Q000187:drug effects; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage* / Q000276:immunology
D000336:Aerosols; D053299:Apolipoprotein B-100; D001057:Apolipoproteins E; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018796:Immunoconjugates; D010446:Peptide Fragments; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D014614:Vaccines, Synthetic; D016753:Interleukin-10; D010047:Ovalbumin; D002772:Cholera Toxin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II