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Atherosclerosis

Table of Contents
  1. General Information
    1. Disease
    2. Introduction
  2. Vaccine Information
    1. human apo B-100 peptide-2 protein vaccine
    2. MDA-modified human apo B-100 peptide Vaccine
  3. References
I. General Information
1. Disease:
Atherosclerosis, arteriosclerotic vascular disease (ASVD)
2. Introduction
Atherosclerosis is an inflammatory disease characterized by endothelial activation and dysfunction, lipid accumulation, monocyte infiltration and differentiation, T-cell infiltration and activation, foam cell formation, and fibrosis in the lesion area. Two of its common final results, coronary and cerebrovascular disease, are the major causes of morbidity worldwide. Nowadays, atherosclerosis is increasingly considered an immune-mediated inflammatory process of the vasculature in which intense immunological activity is occurring. Hypertension, hyperlipidemia, hyperglycemia, diabetes, obesity, cigarette smoking, age, and sex are well-established risk factors for atherosclerosis (Jan et al., 2010).
II. Vaccine Information
1. human apo B-100 peptide-2 protein vaccine
a. Vaccine Ontology ID:
VO_0004275
b. Type:
Subunit vaccine
c. Status:
Research
d. Antigen
Peptide-2, a peptide taken from the sequence of human apo B-100, with an amino acid sequence of ATRFKHLRKYTYNYEAESSS (Chyu et al., 2005).
e. Adjuvant: aluminum vaccine adjuvant
f. Preparation
Peptide antigen was prepared using Imject SuperCarrier EDC kit (Pierce, Rockford, IL) according to manufacturer’s instruction with minor modification. One milligram peptide in 500 μl conjugation buffer was mixed with 2 mg carrier in 200 μl deionized water. This mixture was then incubated with 1 mg conjugation reagent (EDC, 1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide HCl) at room temperature for 2 h followed by dialysis against 0.083 M sodium phosphate, 0.9 M sodium chloride, pH 7.2, solution overnight at 4 °C. The dialyzed conjugate was diluted with Imject dry blend purification buffer to a final volume of 1.5 ml. Alum was used as immunoadjuvant and mixed with peptide conjugate with 1:1 dilution in volume. The amount of peptide in each immunization was 33 μg/100 μl per injection (Chyu et al., 2005).
g. Immunization Route
subcutaneous injection
h. Mouse Response
  • Host Strain: male apo E (−/−) mice
  • Vaccination Protocol: Peptide immunization For early immunization study, male apo E (−/−) mice, maintained on normal chow diet, received subcutaneous primary immunization with peptide-1 (n = 10), peptide-2 (n = 10) or alum alone (n = 9) at 6–7 weeks of age, followed by an intra-peritoneal booster 3 weeks later. Two weeks after booster, diet was switched to high cholesterol chow (0.15% cholesterol, 21% fat, TD 88137, Harlan-Teklad) and continued until sacrifice at the age of 25 weeks. Blood samples were collected by retro-orbital bleeding 2 weeks after booster and at the time of sacrifice. For late immunization study, male apo E (−/−) mice were kept on high cholesterol diet since 6–7 weeks of age. Since peptide-1 immunization did not reduce atherosclerosis (see Result below), peptide-1 was omitted in this part of the study. At 16 weeks of age, mice received subcutaneous primary immunization with peptide-2 or alum alone, followed by an intra-peritoneal booster 3 weeks later. Mice were sacrificed at age of 30 weeks. A separate group of mice were kept on high cholesterol diet and sacrificed at 16 weeks of age to serve as baseline control (Chyu et al., 2005).
  • Efficacy: Peptide-2 immunization reduced aortic atherosclerosis by 40% and plaque inflammation by 80% compared to controls without a reduction in circulating cholesterol levels whereas Peptide-1 immunization had no effect. Peptide-2 immunization also reduced the progression of aortic lesions when mice were immunized at 16 weeks of age, suggesting the possibility of immuno-modulation in treating established atherosclerosis (Chyu et al., 2005).
2. MDA-modified human apo B-100 peptide Vaccine
a. Vaccine Ontology ID:
VO_0004276
b. Type:
Subunit vaccine
c. Status:
Research
d. Antigen
MDA-modified apo B-100 (Fredrikson et al., 2005).
e. Adjuvant: aluminum hydroxide vaccine adjuvant
f. Immunization Route
Intramuscular injection (i.m.)
g. Mouse Response
  • Host Strain: Male apo E0 mice on C57BL/6 background
  • Vaccination Protocol: Mice (n = 8–10 per group) were given a first injection with a MDA modified peptide conjugated to the carrier or the carrier alone at 6 weeks of age and booster injections 3 and 5 weeks later. Each injection contained 50 mg of the MDA-modified peptide conjugated to 50mg of the carrier cBSA (cationized bovine serum albumin) dissolved in 0.083M sodium phosphate 0.9M NaCl pH 7.2, according to the manufacture’s protocol (No. 77652, Pierce, Rockford, IL, USA), and with Alum (aluminum hydroxide, Pierce) included in all injections as adjuvant. The mice were fed a cholesterol diet (0.15% cholesterol, 21% fat; Lactamin AB, Kimstad, Sweden) from the age of 10 weeks (Fredrikson et al., 2005).
  • Efficacy: Immunization with fragment P45 reduced atherosclerosis with 48%; fragment P74with 31; whereas immunization with P240 had no effect (Fredrikson et al., 2005).
III. References
1. Chyu et al., 2005: Chyu KY, Zhao X, Reyes OS, Babbidge SM, Dimayuga PC, Yano J, Cercek B, Fredrikson GN, Nilsson J, Shah PK. Immunization using an Apo B-100 related epitope reduces atherosclerosis and plaque inflammation in hypercholesterolemic apo E (-/-) mice. Biochemical and biophysical research communications. 2005; 338(4); 1982-1989. [PubMed: 16288717].
2. Fredrikson et al., 2005: Fredrikson GN, Andersson L, Söderberg I, Dimayuga P, Chyu KY, Shah PK, Nilsson J. Atheroprotective immunization with MDA-modified apo B-100 peptide sequences is associated with activation of Th2 specific antibody expression. Autoimmunity. 2005; 38(2); 171-179. [PubMed: 16040338].
3. Jan et al., 2010: Jan M, Meng S, Chen NC, Mai J, Wang H, Yang XF. Inflammatory and autoimmune reactions in atherosclerosis and vaccine design informatics. Journal of biomedicine & biotechnology. 2010; 2010; 459798. [PubMed: 20414374].