Vaccination against TIE2 reduces atherosclerosis.
BACKGROUND
TIE2(+) cells play a crucial role in processes that are involved in atherosclerosis, such as angiogenesis. Therefore, the specific deletion of TIE2(+) cells by means of DNA vaccination may affect atherosclerosis.


METHODS
Cellular immunity against cells that overexpress TIE2 was established in LDLr(-/-) mice by a novel oral DNA vaccination technique, in which an attenuated Salmonella typhimurium strain was used as a carrier for plasmid pcDNA3.1 encoding TIE2. After three oral vaccinations with 2-week time intervals LDLr(-/-) mice were put on a Western type diet and atherosclerosis was induced.


RESULTS
Eight weeks after vaccination FACS analysis of circulating peripheral blood mononuclear cells (PBMCs) revealed a significant decrease (33%, p<0.05) in TIE2(+) cells upon vaccination against TIE2, indicating the successful induction of cellular immunity following vaccination against TIE2. Six weeks after collar placement vaccination against TIE2 resulted in significantly decreased carotid atherosclerosis, as indicated by 30% (p<0.05) reduced intima area and 27% (p<0.05) reduced intima/lumen ratios. Furthermore, atherosclerosis was attenuated in the aortic root by 42% (p<0.05), further underlining the anti-atherosclerotic effect of vaccination against TIE2. Adventitial angiogenesis was reduced by 61% (p<0.05) upon vaccination against TIE2 providing a mechanism via which vaccination against TIE2 inhibits lesion formation. Histochemical analysis of the atherosclerotic lesion composition revealed a 1.6-fold (carotid artery, p<0.05) and 1.9-fold (aortic root, p<0.05) increase in collagen content upon vaccination against TIE2, indicating a more stable plaque phenotype.


CONCLUSIONS
We demonstrate that vaccination against TIE2 induces cellular immunity against cells that overexpress TIE2 and results in smaller atherosclerotic lesions with a more stable phenotype. Therefore, vaccination strategies that target cells that contribute to atherosclerosis, may be of potential use in the development of novel treatments of atherosclerosis.
Hauer
Arnaud D
AD
Division of Biopharmaceutics, Leiden University, 2333 CC, Leiden, The Netherlands. A.Hauer@LACDR.leidenuniv.nl
Habets
Kim L L
KL
van Wanrooij
Eva J A
EJ
de Vos
Paula
P
Krueger
Joerg
J
Reisfeld
Ralph A
RA
van Berkel
Theo J C
TJ
Kuiper
Johan
J
D000284:Administration, Oral; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D007111:Immunity, Cellular; D007115:Immunization Schedule; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control; D010641:Phenotype; D042787:Receptor, TIE-2 / Q000235:genetics / Q000276:immunology*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012486:Salmonella typhimurium / Q000235:genetics; D014613:Vaccines, Attenuated / Q000008:administration & dosage; D019444:Vaccines, DNA / Q000008:administration & dosage*
D011973:Receptors, LDL; D014613:Vaccines, Attenuated; D019444:Vaccines, DNA; D003094:Collagen; D042787:Receptor, TIE-2