title: Induction of anti-anti-idiotype antibodies against sulfated glycosaminoglycans reduces atherosclerosis in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  The pathogenesis of atherosclerosis is associated with the early retention of low-density lipoproteins that are trapped in the extracellular matrix of the arterial intima by interaction with glycosaminoglycan side chains of proteoglycans. Mutant mouse/human chimeric antibodies of the murine monoclonal antibody P3, which react with N-glycolyl-containing gangliosides and sulfated glycosaminoglycans, were tested for their potentially antiatherogenic properties through the induction of an idiotypic antibody network that may specifically interfere with the binding of low-density lipoproteins to proteoglycan side chains, low-density lipoprotein modification, and foam cell formation.
  
  
  RESULTS
  Apolipoprotein E-deficient mice fed a high-fat, high-cholesterol diet received 5 to 6 doses of chP3R99 or chP3S98 mutant antibodies, showing high and low reactivity, respectively, against their respective antigens. Both chimeric antibodies elicited an immunodominant anti-idiotypic response in the absence of adjuvant. A striking (40%-43%) reduction (P<0.01) in total lesion areas was observed in 18-week-old mice immunized with chP3R99, but not chP3S98, compared with PBS-treated mice. The antiatherosclerotic effect was associated with increased mice sera reactivity against heparin and sulfated glycosaminoglycans, including chondroitin and dermatan sulfate. In addition, purified IgG from chP3R99-immunized mice blocked the retention of apolipoprotein B-containing lipoproteins within the arterial wall of apolipoprotein E(-/-) mice.
  
  
  CONCLUSIONS
  The present study supports use of active immunization and the mounting of an idiotypic antibody network response against glycosaminoglycans as a novel approach to target atherosclerosis.
authors.affiliation: Division of Immunobiology, Center of Molecular Immunology, 216 St and 15th Ave, Siboney, Playa PO Box 16040, Havana 11600, Cuba.
authors.forename: Víctor
authors.initials: V
authors.lastname: Brito
authors.forename: Katia
authors.initials: K
authors.lastname: Mellal
authors.forename: Simon Giroux
authors.initials: SG
authors.lastname: Portelance
authors.forename: Arlenis
authors.initials: A
authors.lastname: Pérez
authors.forename: Yosdel
authors.initials: Y
authors.lastname: Soto
authors.forename: Denis
authors.initials: D
authors.lastname: deBlois
authors.forename: Huy
authors.initials: H
authors.lastname: Ong
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marleau
authors.forename: Ana María
authors.initials: AM
authors.lastname: Vázquez
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001158:Arteries / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D006025:Glycosaminoglycans / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050506:Mutant Chimeric Proteins / Q000276:immunology / Q000627:therapeutic use; D013431:Sulfates / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D006025:Glycosaminoglycans; D008077:Lipoproteins, LDL; D050506:Mutant Chimeric Proteins; D013431:Sulfates