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DNA vaccination with heat shock protein 60 inhibits cyclophosphamide-accelerated diabetes.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2002 Nov 15; Vol. 169 (10), pp. 6030-5. - Publication Year :
- 2002
-
Abstract
- Nonobese diabetic (NOD) mice spontaneously develop diabetes as a consequence of an autoimmune process that can be inhibited by immunotherapy with the 60-kDa heat shock protein (hsp60), with its mycobacterial counterpart 65-kDa (hsp65), or with other Ags such as insulin and glutamic acid decarboxylase (GAD). Microbial infection and innate signaling via LPS or CpG motifs can also inhibit the spontaneous diabetogenic process. In addition to the spontaneous disease, however, NOD mice can develop a more robust cyclophosphamide-accelerated diabetes (CAD). In this work, we studied the effect on CAD of DNA vaccination with constructs encoding the Ags human hsp60 (phsp60) or mycobacterial hsp65 (phsp65). Vaccination with phsp60 protected NOD mice from CAD. In contrast, vaccination with phsp65, with an empty vector, or with a CpG-positive oligonucleotide was not effective, suggesting that the efficacy of the phsp60 construct might be based on regulatory hsp60 epitopes not shared with its mycobacterial counterpart, hsp65. Vaccination with phsp60 modulated the T cell responses to hsp60 and also to the GAD and insulin autoantigens; T cell proliferative responses were significantly reduced, and the pattern of cytokine secretion to hsp60, GAD, and insulin showed an increase in IL-10 and IL-5 secretion and a decrease in IFN-gamma secretion, compatible with a shift from a Th1-like toward a Th2-like autoimmune response. Our results extend the role of specific hsp60 immunomodulation in the control of beta cell autoimmunity and demonstrate that immunoregulatory networks activated by specific phsp60 vaccination can spread to other Ags targeted during the progression of diabetes, like insulin and GAD.
- Subjects :
- Amino Acid Sequence
Animals
Cells, Cultured
Chaperonin 60 administration & dosage
Chaperonin 60 genetics
Chaperonins administration & dosage
Chaperonins genetics
Chaperonins immunology
Diabetes Mellitus, Type 1 chemically induced
Diabetes Mellitus, Type 1 enzymology
Diabetes Mellitus, Type 1 immunology
Disease Progression
Female
Glutamate Decarboxylase pharmacology
Humans
Injections, Intramuscular
Insulin pharmacology
Interferon-gamma metabolism
Lymphocyte Activation drug effects
Lymphocyte Activation immunology
Mice
Mice, Inbred NOD
Molecular Sequence Data
Mycobacterium tuberculosis immunology
T-Lymphocytes enzymology
T-Lymphocytes immunology
T-Lymphocytes metabolism
Vaccines, DNA administration & dosage
Vaccines, DNA genetics
Bacterial Proteins
Chaperonin 60 immunology
Cyclophosphamide administration & dosage
Cyclophosphamide antagonists & inhibitors
Diabetes Mellitus, Type 1 prevention & control
Vaccines, DNA immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 169
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 12421990
- Full Text :
- https://doi.org/10.4049/jimmunol.169.10.6030