Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens.
A peptide of the human 60-kDa heat-shock protein (hsp60), designated p277, was found to be useful as a therapeutic agent to arrest the autoimmune process responsible for diabetes in nonobese diabetic (NOD) mice. The effectiveness of peptide treatment was associated with the induction of peptide-specific antibodies of the IgG1 but not of the IgG2a isotype, suggesting the possibility that a Th2-type response may have been induced. We now report that the effectiveness of p277 treatment is associated with the transient activation of anti-p277 splenic T-cells that produce the Th2 cytokines interleukin-4 (IL-4) and IL-10. The Th2 response to p277 was associated with reduced Th1-type autoimmunity to hsp60 and to two other target antigens associated with diabetes: GAD and insulin. The Th2 shift appeared to be relatively specific; spontaneous T-cell reactivity to a bacterial antigen peptide remained in the Th1 mode in the p277-treated mice. Moreover, treatment with the bacterial peptide did not induce a change in cytokine profile, and it did not affect progression of the disease. Thus, effective peptide treatment of the diabetogenic process associated with the induction of antibodies may be explained by selective and transient activation of Th2 autoimmune reactivity.
Elias
D
D
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Meilin
A
A
Ablamunits
V
V
Birk
O S
OS
Carmi
P
P
Könen-Waisman
S
S
Cohen
I R
IR
D000818:Animals; D000918:Antibody Specificity; D000941:Antigens / Q000276:immunology*; D001323:Autoantibodies / Q000187:drug effects; D015551:Autoimmunity; D018834:Chaperonin 60; D016207:Cytokines / Q000187:drug effects / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006360:Heat-Shock Proteins / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000378:metabolism*
D000941:Antigens; D001323:Autoantibodies; D018834:Chaperonin 60; D016207:Cytokines; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; C095402:peptide 277, heat shock protein 60