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P.K.Shah, MD Director, Division of Cardiology and Atherosclerosis Research Center Cedars Sinai Medical Center, Los Angeles Immunomodulation of Atherosclerosis” Immunomodulation of Atherosclerosis” AEHA-AHA-Nov 12-2005, Dallas

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P.K.Shah, MDDirector, Division of Cardiology and

Atherosclerosis Research CenterCedars Sinai Medical Center, Los Angeles

““Immunomodulation of Atherosclerosis”Immunomodulation of Atherosclerosis”

AEHA-AHA-Nov 12-2005, Dallas

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“Vaccines for infectious diseasesare likely to be the most important medical contribution to public health during the last 100 years -------------”

Nilsson J , Hansson G K , Shah PK: ATVB 2004; 25: 1-11

Vaccine for Atherosclerosis

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Yin and the Yang of Immune System in Atherosclerosis

Adaptive ImmunityInnate Immunity

Toll like receptors(TLR) Scavenger Receptors

(SR-A, CD 36)T-cells B-cells

MacrophagesDendritic Cells

CRPNaturalAntibody

Immune Activation in AtherosclerosisImmune Activation in Atherosclerosis

Auto-antigens Consequences of Immune Response

Hsp-60: Pro-atherogenic 2GP1 : Pro-atherogenic ox-LDL: ???

Both innate and adaptive immune responses modulate atherosclerosis

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Apo B100

Cholesterol

LDL cholesterol

Apo B100

Cholesterol

Oxidized LDL

Immune Recognition

B-cells T-cells (antibodies) (cytokines)

PlaqueFormation

Immune Response to Oxidized /MDA-LDL

PhospholipidPhospholipid

Macrophage

Phospholipid Apo B 100Neoantigens Neoantigens

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ImmunizedN=9

Immunization of Cholesterol-fed Rabbits with Homologous LDL SubstantiallyImmunization of Cholesterol-fed Rabbits with Homologous LDL SubstantiallyReduces Aortic Atherosclerosis Despite HypercholesterolemiaReduces Aortic Atherosclerosis Despite Hypercholesterolemia

Exte

nt o

f Pla

que

(mm

2 )Ameli, Shah, Nillson et al :ATVB 1996Nilsson , Ameli, Shah et al: JACC 1997

Cholesterol 1259mg/dl 1181mg/dl

ControlN=7

Apo B100

Cholesterol

LDL Cholesterol

Apo B100

Cholesterol

Oxidized LDL

Phospholipid Phospholipid

-Antigen: 280 mcg LDL-Adjuvant: 700 mcg AdjuPrime -Primary SC Vaccination followed by 1 booster-Animals euthanzied 16 weeks after vaccination

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Palinski , Witztum et al : PNAS 1995

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10

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70

Control MDA-LDLRabbits Immunized Rabbits(N=11) (N=14)

Immunization of LDL-Receptor Deficient (Watanabe Rabbits) with Homologous Malondialdehyde (MDA) Modified LDL Reduces Atherogenesis

% of Aortic Surface with Plaque

P<0.005

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Apo B100

LDL Cholesterol

Cholesterol

302 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

( Collaborative Research Program between Cedars Sinai Medical Center (P.K.Shah) and

University of Lund (Jan Nilsson) )

Hypothesis: Specific antigenic epitopes on Apo B 100 component of LDL provoke athero-protective immune response

Phospholipid

ATVB 2003

Peptide 143 + Peptide 210 Mixture

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Immunization of Apo E Null Mice with Apo B-100 related Peptide Sequence Reduces Atherosclerosis

EEEMLENVSLVCPKDATRFK

ATRFKHLRKYTYNYQAQSSS

Peptide 1

Peptide 2

Mouse Apo B 100 Homology

75%

85%

Alum used as adjuvant

6-7 wks 8-9 wks 25 wksIst vaccination Booster Sacrifice

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Immunization of Apo E Null Mice with Apo B-100 related Peptide Sequence : Effect on Cholesterol Levels and Aortic Atherosclerosis

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200

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600

800

1000

1200

1400

1600

Alum(Control)

Peptide 1 Peptide 2

Serum cholesterol mg/dl

Immunization Group

N=9 N=10 N=100

0.5

1

1.5

2

2.5

3

3.5

Alum(Control)

Peptide 1 Peptide 2

% of Aortic Surface Covered by Plaque

Immunization Group

P<0.01

N=9 N=10 N=10

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Immunization of Apo E Null Mice with Apo B-100 related Peptide Sequence Reduces Atherosclerosis

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Immunization of Apo E Null Mice with Apo B-100 related Peptide Sequence Reduces Plaque Inflammation and Increases Collagen Content

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Alum(Control)

Peptide 1 Peptide 2

% Macrophage immunoreactivity

Immunization Group

p<0.05

N=9 N=10 N=10 0

5

1015

2025

3035

40

45

Alum(Control)

Peptide 1 Peptide 2

% Collagen content (Trichrome)

Immunization Group

p<0.05

N=9 N=10 N=10

Immunization Group:

Late Immunization of Apo E Null Mice with Apo B-100 related Peptide Sequence Attenuates Progression of Atherosclerosis

0

2

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Alum Ctl Peptide 2

% Aortic Surface with Plaque

16 wk 30 wk 16 wk 30 wk

Cholesterol (mg/dl): 1274 930 1274 989

P<0.05

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0.5

1

1.5

2

2.5

3

3.5

Mice receivingSplenocytesFrom AlumImmunized mice

% of Aortic Surface Covered by Plaque

P<0.01

N=9 N=9

Mice receivingSplenocytesFrom Peptide 2Immunized mice

Adoptive Transfer of Splenocytes from Peptide 2 Immunized Mice ReducesAtherosclerosis in Recipient Unimmunized Apo E Null Mice

Mice receivingSplenocytesFrom Peptide 1Immunized mice

N=9

Multiple Apo B-100 Related Peptide Antigens HaveAthero-protective Effects in Apo E Null mice

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Control Peptide 45 Peptide 74 Peptide210

Peptide240

Peptides11, 25,74

Peptides30-34

Peptides143,210

% Aortic Atherosclerosis Fredrickson, Shah, Nilsson et al : ATVB 2003

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Conclusions

AcknowledgementsKuang-Yuh Chyu , MD, PhD (Cedars Sinai)

Xiaoning Li, PhD(Cedars Sinai)Juliana Yano,BS (Cedars-Sinai)

Gunilla Nordin-Fredrickson, MD, PhD (Sweden)Jan Nilsson, MD, PhD (Sweden)

-Immune system plays a complex role in atherosclerosis with pro-atherogenic and athero-protective effects

-Immunization using LDL/ox-LDL and specific Apo B-100 related peptide sequences reduces atherosclerosis and favorably modifies plaque composition

- Immunotherapy of atherosclerosis warrants further investigation

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