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

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P.K.Shah, MD Director, Division of Cardiology and Atherosclerosis Research Center

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P k shah md director division of cardiology and atherosclerosis research center

AEHA-AHA-Nov 12-2005, Dallas

“Immunomodulation of Atherosclerosis”

P.K.Shah, MD

Director, Division of Cardiology and

Atherosclerosis Research Center

Cedars Sinai Medical Center, Los Angeles


P k shah md director division of cardiology and atherosclerosis research center

Vaccine for Atherosclerosis

“Vaccines for infectious diseases

are 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


P k shah md director division of cardiology and atherosclerosis research center

Innate Immunity

Yin and the Yang of Immune System in Atherosclerosis

Adaptive Immunity

Macrophages

Dendritic Cells

Natural

Antibody

CRP

Toll like receptors

(TLR)

B-cells

T-cells

Scavenger Receptors

(SR-A, CD 36)


P k shah md director division of cardiology and atherosclerosis research center

Immune Activation in Atherosclerosis

Both innate and adaptive immune responses modulate atherosclerosis

Auto-antigensConsequences of Immune Response

Hsp-60:Pro-atherogenic

2GP1 :Pro-atherogenic

ox-LDL:???


P k shah md director division of cardiology and atherosclerosis research center

Immune Response to Oxidized /MDA-LDL

Apo B100

Apo B100

Cholesterol

Cholesterol

Phospholipid

Phospholipid

Plaque

Formation

LDL cholesterol

Oxidized LDL

Phospholipid Apo B 100

Neoantigens Neoantigens

Immune Recognition

B-cells T-cells

(antibodies) (cytokines)

Macrophage


P k shah md director division of cardiology and atherosclerosis research center

Immunization of Cholesterol-fed Rabbits with Homologous LDL Substantially

Reduces Aortic Atherosclerosis Despite Hypercholesterolemia

Ameli, Shah, Nillson et al :ATVB 1996

Nilsson , Ameli, Shah et al: JACC 1997

Apo B100

Apo B100

Cholesterol

Cholesterol

Phospholipid

Phospholipid

Extent of Plaque (mm2)

Oxidized LDL

LDL Cholesterol

-Antigen: 280 mcg LDL

-Adjuvant: 700 mcg AdjuPrime

-Primary SC Vaccination followed by 1 booster

-Animals euthanzied 16 weeks after vaccination

Control

N=7

Immunized

N=9

Cholesterol

1259mg/dl 1181mg/dl


P k shah md director division of cardiology and atherosclerosis research center

Immunization of LDL-Receptor Deficient (Watanabe Rabbits) with

Homologous Malondialdehyde (MDA) Modified LDL Reduces Atherogenesis

Palinski , Witztum et al : PNAS 1995

% of Aortic Surface with Plaque

P<0.005

Control MDA-LDL

Rabbits Immunized Rabbits

(N=11) (N=14)


P k shah md director division of cardiology and atherosclerosis research center

Apo B100

  • 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) )

Cholesterol

Phospholipid

LDL Cholesterol

Hypothesis: Specific antigenic epitopes on Apo B 100 component of

LDL provoke athero-protective immune response


P k shah md director division of cardiology and atherosclerosis research center

ATVB 2003

Peptide 143 + Peptide 210 Mixture


P k shah md director division of cardiology and atherosclerosis research center

Immunization of Apo E Null Mice with Apo B-100 related

Peptide Sequence Reduces Atherosclerosis

Alum used as adjuvant

Mouse Apo B 100 Homology

75%

Peptide 1

EEEMLENVSLVCPKDATRFK

85%

ATRFKHLRKYTYNYQAQSSS

Peptide 2

6-7 wks8-9 wks25 wks

Ist vaccination Booster Sacrifice


P k shah md director division of cardiology and atherosclerosis research center

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

Effect on Cholesterol Levels and Aortic Atherosclerosis

Serum cholesterol mg/dl

% of Aortic Surface Covered by Plaque

P<0.01

N=10

N=9

N=10

N=9

N=10

N=10

Alum

(Control)

Alum

(Control)

Peptide 1

Peptide 2

Peptide 2

Peptide 1

Immunization Group

Immunization Group


P k shah md director division of cardiology and atherosclerosis research center

Immunization of Apo E Null Mice with Apo B-100 related

Peptide Sequence Reduces Atherosclerosis


P k shah md director division of cardiology and atherosclerosis research center

Immunization of Apo E Null Mice with Apo B-100 related

Peptide Sequence Reduces Plaque Inflammation and Increases Collagen Content

% Collagen content (Trichrome)

% Macrophage immunoreactivity

p<0.05

p<0.05

N=10

N=10

N=9

N=9

N=10

N=10

Alum

(Control)

Alum

(Control)

Peptide 1

Peptide 1

Peptide 2

Peptide 2

Immunization Group

Immunization Group


P k shah md director division of cardiology and atherosclerosis research center

Late Immunization of Apo E Null Mice with Apo B-100 related

Peptide Sequence Attenuates Progression of Atherosclerosis

% Aortic Surface with Plaque

P<0.05

16 wk 30 wk

16 wk 30 wk

Alum Ctl

Peptide 2

Immunization Group:

1274 930 1274 989

Cholesterol (mg/dl):


P k shah md director division of cardiology and atherosclerosis research center

Adoptive Transfer of Splenocytes from Peptide 2 Immunized Mice Reduces

Atherosclerosis in Recipient Unimmunized Apo E Null Mice

% of Aortic Surface Covered by Plaque

P<0.01

N=9

N=9

N=9

Mice receiving

Splenocytes

From Alum

Immunized mice

Mice receiving

Splenocytes

From Peptide 1

Immunized mice

Mice receiving

Splenocytes

From Peptide 2

Immunized mice


Multiple apo b 100 related peptide antigens have athero protective effects in apo e null mice

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

Fredrickson, Shah, Nilsson et al : ATVB 2003

% Aortic Atherosclerosis


P k shah md director division of cardiology and atherosclerosis research center

Conclusions

  • 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

Acknowledgements

Kuang-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)

Michael and Jane Eisner Foundation


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