title: Decrease in blood pressure and regression of cardiovascular complications by angiotensin II vaccine in mice.
abstract: Vaccines have been recently developed to treat various diseases such as cancer, rheumatoid arthritis and Alzheimer's disease in addition to infectious diseases. However, before use in the clinical setting, vaccines targeting self-antigens must be demonstrated to be effective and safe, evoking an adequate humoral immune response from B cells while avoiding T cell activation in response to self. Although the vaccine targeting angiotensin II (Ang II) is efficient in rodents and humans, little is known regarding the immunological activation and safety of the vaccine. In this study, we evaluated the efficiency and safety of an Ang II peptide vaccine in mice. Immunization with Ang II conjugated to keyhole limpet hemocyanin (KLH) successfully induced the production of anti-Ang II antibody, which blocked Ang II signaling in human aortic smooth muscle cells. However, Ang II itself did not activate T cells, as assessed by the proliferation and lymphokine production of T cells in immunized mice, whereas KLH activated T cells. In an Ang II-infused model, the non-immunized mice showed high blood pressure (BP), whereas the immunized mice (Ang II-KLH) showed a significant decrease in systolic BP, accompanied by significant reductions in cardiac hypertrophy and fibrosis. Importantly, anti-Ang II antibody titer was not elevated even after the administration of large amounts of Ang II, indicating that Ang II itself boosted antibody production, most likely due to less activation of T cells. In addition, no accumulation of inflammatory cells was observed in immunized mice, because endogenous Ang II would not activate T cells after immunization with Ang II-KLH. Taken together, these data indicate that vaccines targeting Ang II might be effective to decrease high BP and prevent cardiovascular complications without severe side effects.
authors.affiliation: Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nakagami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koriyama
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Mariana Kiomy
authors.initials: MK
authors.lastname: Osako
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shimamura
authors.forename: Mariko
authors.initials: M
authors.lastname: Kyutoku
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyake
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000804:Angiotensin II / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000276:immunology* / Q000503:physiopathology* / Q000517:prevention & control; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D007114:Immunization; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014612:Vaccines / Q000276:immunology*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D014612:Vaccines; D000804:Angiotensin II
references.citation: J Clin Invest. 2008 Mar;118(3):868-78
references.pmid: 18292809
references.citation: Micron. 1999 Dec;30(6):597-623
references.pmid: 10544506
references.citation: Nature. 1999 Jul 8;400(6740):173-7
references.pmid: 10408445
references.citation: Circ Res. 1957 Mar;5(2):137-43
references.pmid: 13414084
references.citation: Kidney Int. 2009 Sep;76(5):546-56
references.pmid: 19571790
references.citation: Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H1053-61
references.pmid: 21193590
references.citation: Curr Top Microbiol Immunol. 1969;50:78-106
references.pmid: 4190606
references.citation: Circ Res. 1975 Dec;37(6):715-24
references.pmid: 1192566
references.citation: Circulation. 1958 Apr;17(4, Part 2):653-7
references.pmid: 13523775
references.citation: J Hypertens. 2007 Jan;25(1):63-72
references.pmid: 17143175
references.citation: J Immunol. 2005 Feb 1;174(3):1580-6
references.pmid: 15661919
references.citation: Proc Natl Acad Sci U S A. 1987 Jun;84(12):4346-50
references.pmid: 3108891
references.citation: Nat Rev Neurosci. 2002 Oct;3(10):824-8
references.pmid: 12360327
references.citation: Brain Pathol. 2004 Jan;14(1):11-20
references.pmid: 14997933
references.citation: J Exp Med. 1964 Mar 1;119:425-32
references.pmid: 14129713
references.citation: Nat Med. 2003 Apr;9(4):448-52
references.pmid: 12640446
references.citation: Neurology. 2003 Jul 8;61(1):46-54
references.pmid: 12847155
references.citation: Nature. 2000 Dec 21-28;408(6815):982-5
references.pmid: 11140686
references.citation: Circulation. 1990 Jun;81(6):1899-910
references.pmid: 2188756
references.citation: Swiss Med Wkly. 2010 Nov 01;140:w13108
references.pmid: 21043003
references.citation: Kidney Int. 2004 Feb;65(2):521-30
references.pmid: 14717922
references.citation: Cancer Biother Radiopharm. 2011 Feb;26(1):1-64
references.pmid: 21355777
references.citation: Circulation. 2006 Sep 12;114(11):1177-84
references.pmid: 16952986
references.citation: Hum Vaccin. 2009 Feb;5(2):79-84
references.pmid: 18670196
references.citation: Lancet. 2008 Mar 8;371(9615):821-7
references.pmid: 18328929
references.citation: Int Immunol. 2003 Apr;15(4):505-14
references.pmid: 12663680
references.citation: J Immunol. 1999 Apr 1;162(7):3942-9
references.pmid: 10201913
references.citation: Br J Pharmacol. 2000 Mar;129(6):1178-82
references.pmid: 10725266
references.citation: Circ Res. 1963 Mar;12:241-55
references.pmid: 13959243
references.citation: Circ Res. 2010 Aug 20;107(4):466-75
references.pmid: 20595654
references.citation: J Neurosci Res. 2004 Feb 1;75(3):301-6
references.pmid: 14743443
references.citation: Autoimmun Rev. 2010 Nov;10(1):3-7
references.pmid: 20863908
references.citation: Circulation. 1958 Apr;17(4, Part 2):648-52
references.pmid: 13523774
references.citation: Clin Sci (Lond). 2004 Aug;107(2):167-73
references.pmid: 15040783
references.citation: Br J Clin Pharmacol. 2003 Nov;56(5):505-12
references.pmid: 14651724