Inhibition of experimental Sjögren's syndrome through immunization with HSP60 and its peptide amino acids 437-460.
OBJECTIVE
To investigate a potential immunomodulatory effect of the 60-kd heat-shock protein (Hsp60) on experimental spontaneous Sjögren's syndrome (SS).


METHODS
Seven-week-old nonobese diabetic (NOD) mice were immunized with eukaryotic Hsp60 or an Hsp60-derived peptide (amino acid residue [aa] 437-460). At 21 weeks of age, nondiabetic mice were investigated for salivary gland inflammation, exocrine function, and extraglandular disease manifestations. In addition, biomarker profiles comprising 87 analytes in serum and 75 in saliva were analyzed.


RESULTS
In mice immunized with Hsp60 and aa 437-460, SS-related histopathologic features were significantly reduced compared with NOD controls. In addition, 50% of Hsp60-injected mice and 33% of aa 437-460-injected mice retained normal exocrine function. Both treatments induced similar changes in biomarker profiles. Notably, levels of circulating interferon-gamma-inducible 10-kd protein (IP-10) and eotaxin were decreased significantly after treatment. Anti-type 3 muscarinic acetylcholine receptor (anti-M3R) IgG1, interleukin-10, and leptin discriminated best between the different treatment groups. Successful prevention of hyposalivation was accompanied by quantitative alterations in 36 biomarkers, of which 19 mediators of inflammation declined to levels comparable with those found in BALB/c mice. Low secreted vascular endothelial growth factor A was the most accurate predictor of successful prevention of hyposalivation. Low salivary granulocyte chemotactic protein 2 was identified as the best predictor of normal secretory function across the strains.


CONCLUSIONS
Immunization with Hsp60 and its peptide aa 437-460 led to inhibition of SS in NOD mice. Comprehensive analyses revealed specific biomarker signatures capable of predicting treatment group and treatment outcome. Molecules involved in inflammatory chemotaxis, neovascularization, and regulatory pathways caused the differences displayed by the biomarker profiles.
Delaleu
Nicolas
N
The Gade Institute, University of Bergen, Bergen, Norway.
Madureira
Ana Carina
AC
Immervoll
Heike
H
Jonsson
Roland
R
D000596:Amino Acids / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018834:Chaperonin 60 / Q000627:therapeutic use*; D054413:Chemokine CCL11 / Q000097:blood; D054357:Chemokine CXCL10 / Q000032:analysis; D054427:Chemokine CXCL6 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D010455:Peptides / Q000627:therapeutic use*; D012463:Saliva / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000596:Amino Acids; D015415:Biomarkers; D018834:Chaperonin 60; D054413:Chemokine CCL11; D054357:Chemokine CXCL10; D054427:Chemokine CXCL6; D007328:Insulin; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse