Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens

Elias, D.; Meilin, A.; Ablamunits, V.; Birk, O. S.; Carmi, Pnina; Konen-Waisman, S.; Cohen, Irun R.

doi:10.2337/diabetes.46.5.758

Cited by 92 publications

(60 citation statements)

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“…HSP may also participate in other inflammatory and autoimmune processes, and injection with an HSP peptide ameliorates autoimmune diabetes in mice. 29,30 The results in the present study demonstrate that an antigen-specific approach involving mucosal administration of HSP-65 can specifically affect immune variables and decrease both plaque formation and the inflammatory phenotype. Nasal administration was more effective than oral dosing in this regard.…”

Section: Discussionmentioning

confidence: 76%

Mucosal Administration of Heat Shock Protein-65 Decreases Atherosclerosis and Inflammation in Aortic Arch of Low-Density Lipoprotein Receptor-Deficient Mice

et al. 2002

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Background-Increasing evidence supports the involvement of inflammation and immunity in atherogenesis as well as the role of autoimmunity to heat shock proteins (HSPs) in the progression of atherosclerosis. Mucosal administration of autoantigens decreases organ-specific inflammation and disease in several models of autoimmunity (diabetes, arthritis, and encephalomyelitis) and is also being tested in human clinical trials. Methods and Results-We examined the effect of nasal or oral administration of mycobacterial HSP-65 on atherosclerotic lesion formation in mice lacking the receptor for LDL that were maintained on a high-cholesterol diet. Animals were nasally or orally treated for 1 week with HSP-65, and a high-cholesterol diet was started after the last treatment. The mice were mucosally treated once a week for 8 or 12 weeks, at which time pathological analysis was performed. We found a significant decrease in the size of atherosclerotic plaques, a reduction in macrophage-positive area in the aortic arch, increased interleukin-10 expression, and a reduced number of T cells in nasally treated animals compared with control animals. A similar trend was observed in orally treated mice, but it was not significant. Conclusions-Our results demonstrate that nasal vaccination with HSP reduces the inflammatory process associated with atherosclerosis and provides a new immunologic approach for the treatment of atherosclerosis. (Circulation.

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Section: Discussionmentioning

confidence: 76%

Mucosal Administration of Heat Shock Protein-65 Decreases Atherosclerosis and Inflammation in Aortic Arch of Low-Density Lipoprotein Receptor-Deficient Mice

et al. 2002

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“…Of note, one of the three phosphorylated tyrosine residues in c-Maf (Tyr 21 ) Previous studies have demonstrated that induction of Th2 response can prevent NOD mice from developing diabetes (16,17). Our data reveal that diminished tyrosine phosphorylation of c-Maf correlates with poor IL-4 production by Th cells and disease development in NOD mice.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine Phosphorylation of c-Maf Enhances the Expression of IL-4 Gene

Lai

Lin

et al. 2012

The Journal of Immunology

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Maf proteins are involved in a variety of biological processes, such as oncogenesis, lens development, and differentiation. In immune system, c-Maf transactivates IL-4 promoter, and ectopic expression of c-Maf skews primary T cell response toward the Th2 pathway. Numerous transcription factors are subjected to posttranslational modification. In this study, to our knowledge, we show for the first time that c-Maf is subjective to tyrosine phosphorylation in Th cells and that the level of its tyrosine phosphorylation positively correlates with IL-4 expression by peripheral Th cells, but is negatively associated with the severity of disease in NOD mice. c-Maf undergoes tyrosine phosphorylation at Tyr21, Tyr92, and Tyr131 residues in Th2 cells. Furthermore, tyrosine phosphorylation at these three residues is critical for the recruitment of c-Maf to IL-4 promoter and IL-4 production in Th cells. Taken together, this study sheds new light on the role of posttranslational modification of c-Maf in IL-4 production and Th cell-mediated autoimmune diseases.

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“…130 Furthermore, a single intraperitoneal injection with peptide 277 in 4-week old NOD mice could attenuate diabetes incidence, an effect possibly mediated by a transient Th2 burst. [131][132][133] These positive results in NOD mice and the HSP60 T-cell reactivity in recent-onset diabetic patients have highlighted peptide 277 as a possible candidate for Ag-specific clinical studies. 134 In order to stabilize peptide 277 chemically without interfering with its immunomodulatory insulin or pro-insulin respectively.…”

Section: No Effect 109mentioning

confidence: 95%