Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity.
Nonobese diabetic (NOD) mice develop insulitis and diabetes through a process involving autoimmunity to the 60-kDa heat shock protein (HSP60). Treatment of NOD mice with HSP60 or with peptides derived from HSP60 inhibits this diabetogenic process. We now report that NOD diabetes can be inhibited by vaccination with a DNA construct encoding human HSP60, with the pcDNA3 empty vector, or with an oligonucleotide containing the CpG motif. Prevention of diabetes was associated with a decrease in the degree of insulitis and with down-regulation of spontaneous proliferative T cell responses to HSP60 and its peptide p277. Moreover, both the pcDNA3 vector and the CpG oligonucleotide induced specific Abs, primarily of the IgG2b isotype, to HSP60 and p277, and not to other islet Ags (glutamic acid decarboxylase or insulin) or to an unrelated recombinant Ag expressed in bacteria (GST). The IgG2b isotype of the specific Abs together with the decrease in T cell proliferative responses indicate a shift of the autoimmune process to a Th2 type in treated mice. These results suggest that immunostimulation by bacterial DNA motifs can modulate spontaneous HSP60 autoimmunity and inhibit NOD diabetes.
Quintana
F J
FJ
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Rotem
A
A
Carmi
P
P
Cohen
I R
IR
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D018834:Chaperonin 60 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018899:CpG Islands / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000276:immunology; D006360:Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000276:immunology; D007115:Immunization Schedule; D007074:Immunoglobulin G / Q000096:biosynthesis; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology; D015994:Incidence; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology*; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D001324:Autoantigens; C408982:CPG-oligonucleotide; D018834:Chaperonin 60; D006131:Growth Inhibitors; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D019444:Vaccines, DNA; C095402:peptide 277, heat shock protein 60; D016753:Interleukin-10; D007371:Interferon-gamma