Hsp60 Peptide Therapy of NOD Mouse Diabetes Induces a Th2 Cytokine Burst and Downregulates Autoimmunity to Various β-Cell Antigens

Abstract

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.

Cytokine secretion patterns in twins discordant for Type I diabetes

“…For the same two stimuli no difference was seen in IL-10 or IL-4 responses between ICA positive and their respective diabetic cotwins. A Th2 bias of the response to hsp60 in discordant twins of low diabetes risk is consistent with recent studies in NOD mice, where a Th1 bias of the T cell response to hsp60 was found to correlate with disease progression in mice whereas a Th2 bias was found in animals protected from diabetes development [6]. In man, previous studies of a possible association between hsp60 autoimmunity and Type I diabetes did not yield firm conclusions [3,7,8].…”

“…It is therefore conceivable that the immune response to hsp60 is of relevance to the disease process in islets. Recent studies suggest that hsp60 is a unique autoantigen because it not only is recognised by T cells through classic rules of MHC dependent peptide presentation [6] but is also a ªdangerº antigen to the innate immune system. This means, macrophages, endothelial cells and other primitive immune cells are able to recognise exogenous hsp60 and secrete mediators with potent modulatory effects on subsequent T cell responses [10,11].…”

CD8+T cells control the TH phenotype of MBP-reactive CD4+T cells in EAE mice

“…Furthermore, analogous to the 1-9Nac MBP-induced resistance in EAE mice, immunizing NOD mice with p277 peptide clinically arrested the autoimmune diabetic process. Interestingly, the effectiveness of this peptide treatment was associated with the transient activation of anti-p277 splenic TH2 cells (39). A similar observation was also made by Chaturvedi et al (40), when immunizing NOD mice with a different self-peptide I-A␤ g7 54-76.…”

Type 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model

“…These include islet-specific Ags, like insulin, and other nonislet-specific Ags, like glutamic acid decarboxylase (GAD) 3 65, carboxypeptidase H, and IA-2 among others (11,12). Of all the known autoantigens implicated in the disease process, treatment with only insulin, GAD 65, and the heat shock protein (hsp) 60 peptide p277 can protect nonobese diabetic (NOD) mice from disease (13)(14)(15)(16). Insulin and GAD 65 are also the most prominent islet autoantigens shown to be recognized by peripheral T cells from type 1 diabetes patients (17,18).…”