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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. 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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  1. 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

  2. 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

  3. 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)

  4. Immune Activation in Atherosclerosis Both innate and adaptive immune responses modulate atherosclerosis Auto-antigens Consequences of Immune Response Hsp-60: Pro-atherogenic 2GP1 : Pro-atherogenic ox-LDL: ???

  5. 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

  6. 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

  7. 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)

  8. 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

  9. ATVB 2003 Peptide 143 + Peptide 210 Mixture

  10. 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

  11. 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

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

  13. 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

  14. 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):

  15. 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

  16. Multiple Apo B-100 Related Peptide Antigens HaveAthero-protective Effects in Apo E Null mice Fredrickson, Shah, Nilsson et al : ATVB 2003 % Aortic Atherosclerosis

  17. 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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