Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis

Arnon Afek, Jacob George, Boris Gilburd, Lubica Rauova, Iris Goldberg, Juri Kopolovic, Dror Harats, Yehuda Shoenfeld

Research output: Contribution to journalArticlepeer-review

Abstract

Heat shock proteins are a family of approximately 25 highly conserved proteins upregulated in response to various forms of stress. They play an active role in the development autoimmtme diseases in animals, and have been incriminated in human autoimmune diseases (i.e. rheumatoid arthritis, multiple sclerosis). It has been previously shown, that an induced immune response against Heat shock protein 65 (HSP-65) results in atherosclerotic lesions in normocholesterolemic rabbits. We have supported these findings showing that C57BL/6 mice immunized with HSP-65 and fed a high-fat diet develop enhanced fatty streaks. To create a model that will eliminate the need for exogenous supplementation of a high-fat diet, we have immunized LDL receptor deficient (LDL-RD) mice with HSP-65 or with heat-killed Mycobacterium tuberculosis (Mt). Seven groups of LDL-RD mice (n=10), were immunized subcutaneously with different concentrations of HSP-65, Mt or bovine serum albumin (BSA). All mice were fed a normal chow-diet for 3 months. The mice immunized with the higher doses of Mt developed significantly larger fatty streaks when compared with their BSA immunized littermates. The size of the lesions in the aortic sinus were: 31,562 ± 5,994 μm2 in the 10 μg Mt and 52,777 ± 5,245 μm2 in the 100 μg Mt vs. 11,500 ± 3,750 μm2 in the BSA group (P<0.05). In the HSP-65-immunized mice, only the group injected with the highest dose (5 μg, twice) developed significantly larger fatty streaks when compared with the BSA-immunized group (28,611 ± 4,716 μm2 vs. 11,500 ± 3,750 μm2 respectively, (P<0.05). The HSP-65-but not the Mt- or BSA-immunized mice developed high titers of anti HSP-65 antibodies, beginning 10 days after the immunization, which persisted until they were killed. Immunohistochemical staining showed CD3-positive lymphocytes in the aortic sinus of mice immunized with Mt or HSP-65, but not in the control group. Thus, we established a mouse model of HSP-65 immune mediated atherosclerosis devoid of high fat diet supplementation. This model will enable us to further study the role of the immune system in atherosclerosis, via HSP-65 and raise novel immunomodulatory therapeutic modalities. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)115-121
Number of pages7
JournalJournal of Autoimmunity
Volume14
Issue number2
DOIs
StatePublished - 2000

Keywords

  • Atherosclerosis
  • Autoantibody
  • HSP-65
  • LDL-RD mice
  • OxLDL

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