Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice.
BACKGROUND
Increasing evidence supports the involvement of inflammation and immunity in atherogenesis as well as the role of autoimmunity to heat shock proteins (HSPs) in the progression of atherosclerosis. Mucosal administration of autoantigens decreases organ-specific inflammation and disease in several models of autoimmunity (diabetes, arthritis, and encephalomyelitis) and is also being tested in human clinical trials.


RESULTS
We examined the effect of nasal or oral administration of mycobacterial HSP-65 on atherosclerotic lesion formation in mice lacking the receptor for LDL that were maintained on a high-cholesterol diet. Animals were nasally or orally treated for 1 week with HSP-65, and a high-cholesterol diet was started after the last treatment. The mice were mucosally treated once a week for 8 or 12 weeks, at which time pathological analysis was performed. We found a significant decrease in the size of atherosclerotic plaques, a reduction in macrophage-positive area in the aortic arch, increased interleukin-10 expression, and a reduced number of T cells in nasally treated animals compared with control animals. A similar trend was observed in orally treated mice, but it was not significant.


CONCLUSIONS
Our results demonstrate that nasal vaccination with HSP reduces the inflammatory process associated with atherosclerosis and provides a new immunologic approach for the treatment of atherosclerosis.
Maron
Ruth
R
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, USA.
Sukhova
Galina
G
Faria
Ana-Maria
AM
Hoffmann
Ethan
E
Mach
Francois
F
Libby
Peter
P
Weiner
Howard L
HL
D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000009:adverse effects; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001426:Bacterial Proteins; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D018834:Chaperonin 60; D018833:Chaperonins / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D002791:Cholesterol, Dietary; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control*; D008198:Lymph Nodes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009161:Mycobacterium / Q000276:immunology; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018834:Chaperonin 60; D002791:Cholesterol, Dietary; D016207:Cytokines; D011973:Receptors, LDL; C074119:heat-shock protein 65, Mycobacterium; D005620:Freund's Adjuvant; D018833:Chaperonins