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SHAPE Scientific Symposium, Dallas, TX 2013 Concept of a Vaccine for Vascular Disease Modulating Autoimmunity in Atherosclerosis Using a Vaccine Kuang-Yuh Chyu, MD, PhD Associate Director, CICU Cedars Sinai Heart Institute Cedars-Sinai Medical Center.

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SHAPE Scientific Symposium, Dallas, TX 2013

Concept of a Vaccine for Vascular Disease

Modulating Autoimmunity in Atherosclerosis

Using a Vaccine

Kuang-Yuh Chyu, MD, PhD

Associate Director, CICU

Cedars Sinai Heart Institute

Cedars-Sinai Medical Center

Disclosures: Co-Inventor of ApoB-100 Peptide Vaccines for Atherosclerosis.

Patent rights are assigned to Cedars-Sinai Medical Center.


Atherosclerosis is an Auto-Immune Mediated Inflammatory Disease

Pro-atherogenic Adaptive Immunity

APC

Inflammatory

Cytokines

IFN- γ and TNF-α

Th1

Auto

antigen

NKT

MHC/CD1

Atherosclerosis

Naïve

T cell

Inflammatory

Cytokine

IL 17

Th 17

Activated CD4+ T-cell


Athero-protective Adaptive Immune Response Disease

Treg

Antigen

Suppression of

Autoimmune Response

APC

Regulatory T cell

CD25+, Foxp3+

Secrete anti-inflammatory cytokines

IL-10/TGF-β

Naive

T cell

Th1

Tolerogenic

Dendritic Cell

Athero-protective

Effect


Oxidized LDL in Human Coronary Plaques Disease

Colocalizing with Macrophages

Auto-antigens

in

Atherosclerosis

LDL/Ox-LDL

Hsp-60

2GP1

OxLDL

Macrophages


Would Immunization with LDL/oxLDL Disease

Worsen or Reduce

Atherosclerosis?


Immunization of Cholesterol-fed Rabbits with Homologous LDL Reduces Aortic Atherosclerosis Despite Hypercholesterolemia

Extent of Plaque (mm2)

P<0.05

Control

N=7

Immunized

N=9

Ameli, Shah, Nillson et al: ATVB 1996

Nilsson, Ameli, Shah et al: JACC 1997

Cholesterol

1259 mg/dl 1181 mg/dl


Effect of Immunization with Native and Oxidized Homologous LDL On Experimental Atherosclerosis in Hypercholesterolemic Mice

Immunization of LDL-R null mice with homologous native or MDA-LDL reduces atherosclerosis (Freigang et al ATVB 1998)

Immunization of apo E null mice with homologous MDA-LDL reduces atherosclerosis (George et al : Atherosclerosis 1998)

Timing affects the athero-protective effects of LDL-immunization (Chyu, Shah et al. Atherosclerosis 2004)


Apo B-100 LDL On Experimental Atherosclerosis in Hypercholesterolemic Mice

550kD

4536 AA

  • Peptides, 20 amino acids long with 5 amino acid overlap simulating the entire amino acid sequence of human Apo B 100 were synthesized.

  • Using an ELISA with peptides sequences as antigens, antibodies to 101 of these peptide sequences were identified in pooled human sera

  • Several peptide sequences were then used to create vaccines for Immunization in apo E null mice fed a high cholesterol diet

Amino acid 3136-3155

KTTKQ SFDLS VKAQY KKNKH

p210

Johs, A. et al. JBC 2006;281:19732-19739


Apo B100 Related Peptide (p210) Vaccine Reduces Atherosclerosis in Hyperlipidemic Mice

61%

Chyu KY, Shah PK et al: PLoS One 2012

P210: apo B-100 amino acids 3136-3155


Apo B100 Related Peptide (p210) Vaccine Reduces Plaque Macrophages in ApoE-/- Mice

* p<0.05

PBS Adjuvant p210

Control Control Vaccine

Chyu KY, Shah PK et al: PLoS One 2012


Apo B100 Related Peptide (p210) Vaccine Reduces Plaque Dendritic Cells in ApoE-/- Mice

p < 0.05

PBS Adjuvant p210

Control Control Vaccine

Chyu KY, Shah PK et al: PLoS One 2012


Adoptive Transfer of CD8 T-cells from p210 Immunized Mice Conveys Athero-protection to Unimmunized Mice

p < 0.05

Chyu KY et al : PLoS One 2012


Adoptive Transfer of p210 loaded Dendritic Cells reduces Atherosclerosis in Apo E-/- Mice

Nasal delivery of p210-CTB Fusion Construct reduces Atherosclerosis in Apo E-/- Mice

Prolonged subcutaneous delivery of p210 reduces Atherosclerosis in Apo E-/- Mice


Abdominal aortic aneurysm formation after AngII infusion in apoE-/- mice

Daugherty et al Br J Pharmacol. 2001 October; 134(4): 865–870.


% Total Aneurysmal Segment apoE-/- mice

number of aneurysmal segment/number of total segment (%)

1

2

(Aneurysmal segment = diameter>1.35mm)

3

4

p<0.05

5

8

6

7

Number of aneurysmal segment (severity of disease) was significantly reduced in p210 immunized mice.

Honjo T: Circulation (abst) 2011


P210 vaccine reduces mortality in angiotensinii induced aneurysm model in apoe mice
p210 Vaccine Reduces Mortality in AngiotensinII Induced Aneurysm Model in ApoE-/- Mice

Survival Curve

Mortality

P210 = 6.2%

PBS = 32.1%

cBSA = 29.7%

p<0.05 vs. PBS

p<0.05 vs. cBSA by Logrank test

Honjo T: Circulation (abst) 2011


p210 Vaccine Reduces Pro-inflammatory IL-17 Positive CD4 T cells

*

*

CD4+IL-17A+

p < 0.05

N: PBS=8, cBSA=6, p210=6

Honjo T et al : unpublished data 2013


P<0.05 cells

AngII

P<0.05

AngII

Honjo T: Circulation (abst) 2011


P210 Vaccine Reduces AT1R Expression in Aorta cells

IB; AT1R

IB; GAPDH

N=6, P<0.05

PBS

cBSA

p210

p210 vaccine reduced the expression of AT1R in whole aorta.

Honjo T: Circulation (abst) 2011


Conclusions
Conclusions cells

  • Immunization with selected ApoB-100 peptides reduces atherosclerosis and favorably modifies plaque phenotype in hypercholesterolemic mice.

  • Immunization with selected ApoB-100 peptides also reduced AngII induced hypertension and aneurysm formation and mortality due to rupture.

  • These experimental observations provide proof of concept regarding the feasibility and efficacy of apoB-100 peptide based vaccine for vascular diseases.


Lund University, Sweden cells

Oppenheimer Atherosclerosis Research Center

Jan Nilsson, MD, PhD

GN Fredriksson,PhD

Cardiovax

P.K.Shah, MD

Kuang-Yuh Chyu, MD, PhD

Paul Dimayuga,PhD

Tomoyuki Honjo, MD,PhD

Xiaoning Zhao,PhD

Jianchang Zhou, PhD

Nicole Lio

Bojan Cercek, MD, PhD

Cheryl Chan

Juliana Yano

Funding

NIH-NHLBI

Eisner Foundation

Cardiovax

The HeartFoundation

Spielberg Foundation

Corday Foundation


Potential Mechanisms of Action of p210 Vaccine cells

Increased Lysis of

APC

p210

Suppression

of

Antigen Specific

adverse

Autoimmune Response

APC

CD8+ Regulatory T cell

CD25+, IL-10+

CD8+T cell


IL-17 Deletion Protects Mice from AngiotensinII Induced Aortic Aneurysm Formation

Survival

Incidence

0%

46.7%

Honjo T et al : unpublished data 2013


Abdominal Aortic Aneurysm Aortic Aneurysm Formation

Pathophysiology

Inflammation

Immune activation

Oxidative stress

Matrix proteolysis

SMC death


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