Heat-shock proteins induce T-cell regulation of chronic inflammation

Eden, Willem van; Zee, Ruurd van der; Prakken, Berent J.

doi:10.1038/nri1593

Cited by 491 publications

(405 citation statements)

References 151 publications

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“…Other studies show that induction of self-Hsp60 and self-Hsp70 T cell reactivity can control pro-inflammatory responses by production of regulatory Th2-type cytokine responses and CD4 + CD25 + regulatory T cells (reviewed in [24,25]). In patients with juvenile idiopathic arthritis, reactivity towards Hsp60 was increased in patients with a favorable prognosis, which might contribute to immunoregulation and remission of disease [38].…”

Section: Discussionmentioning

confidence: 99%

“…Our results confirm and extend, in a human antigen-specific setting, previous results in the murine system which demonstrated an enhanced immunogenicity of MHC class IIrestricted peptides complexed with HSP. Given the different associations of HSP and autoimmunity [17,[23][24][25], we postulate the hypothesis that the presence of HSP, e.g. after cell death, might be involved in the initiation of autoimmunity by facilitating an immune reaction to a possible autoantigenic peptide at concentrations where peptide without HSP would not be immunogenic at all.…”

Section: Introductionmentioning

confidence: 98%

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The heat shock protein Hsp70 enhances antigen-specific proliferation of human CD4+ memory T cells

et al. 2005

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Heat shock proteins (HSP) can interact with a wide variety of peptides and the resulting HSP:peptide complexes are known to be highly immunogenic. The ability of HSP:peptide complexes to elicit CD8 + T cell responses by cross-presentation of exogenous antigen via MHC class I is well known. In contrast, their role in the activation of CD4 + T cells is less clearly defined, although several recent studies in mice and T cell lines suggest an involvement of HSP in the presentation of antigenic peptides via MHC class II. In this study we have investigated the potential of antigenic peptides from tetanus toxin and influenza hemagglutinin complexed to the human stress-inducible Hsp70 to enhance activation and proliferation of human memory CD4 + T cells. Hsp70:peptide complexes were found to amplify the proliferation of antigen-specific CD4 + T cells as confirmed by HLA-DR tetramer staining. Complex formation of the antigenic peptide with Hsp70 was absolutely required to elicit an antigen-specific amplification. This effect was most pronounced at low doses of antigen and decreasing APC/CD4 + T cell ratios. Taken together, we show the potential of Hsp70 to enhance antigen-specific CD4 + T cell proliferation and to increase the immunogenicity of presented peptides in human CD4 + T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

The heat shock protein Hsp70 enhances antigen-specific proliferation of human CD4+ memory T cells

et al. 2005

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“…For several reasons, Hsp60 can be considered to be a prime candidate for antigen-specific immune therapy in RA (24). First, experiments in the adjuvantinduced arthritis model suggest that Hsp60 might play a crucial role in the immune regulation of arthritis (25).…”

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confidence: 99%

“…In RA, T cells stimulated with human Hsp60 display a marked suppressive phenotype, compared with T cells stimulated with homologous mycobacterial Hsp65 (26). Thus, Hsp60 self-reactive T cells may play a role in modulating chronic arthritis (adjuvant-induced arthritis, RA, and JIA), underscoring their potential as candidate antigens to modulate the immune response in chronic arthritis (24,30).…”

mentioning

confidence: 99%

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

Jong¹,

Lafeber²,

Jager³

et al. 2009

Arthritis & Rheumatism

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Objective. Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60-directed responses in RA, it is necessary to study such responses at the molecular, epitope-specific level. This study was undertaken to characterize the disease specificity and function of pan-DR-binding Hsp60-derived epitopes as possible modulators of autoimmune inflammation in RA.Methods. Lymphocyte proliferation assays (using 3 H-thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls. Results. A disease (RA)-specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), and IL-10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4؉ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5-10-fold higher IL-10:TNF␣ ratio, compared with that of the microbial peptides.Conclusion. These results suggest a diseasespecific immune-modulatory role of epitope-specific T cells in the inflammatory processes of RA. Therefore, these pan-DR-binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy.

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“…First, the lack of a strong Th1 response to Hsp65 in these patients suggests that they were unable to mount a proinflammatory immune response to the vaccine antigen; therefore, the development of autoreactivity and/or pathogenic autoimmunity due to crossrecognition of Hsp65 and Hsp60 was unlikely. Second, although in animal models, injection of mycobacterial products can induce proinflammatory autoimmune clones that recognize Hsp65, 30,31 immunization with purified protein or even with DNA-hsp65 itself, seems almost invariably to induce protection against autoimmune disease, 29,30,32 with the possible exception of two highly susceptible animal models. 33,34 Taken together, our results show that, although our measurements were able to detect some degree of immunostimulation by DNA-hsp65, we were unable to differentiate between patients with different clinical outcomes based on the parameters measured.…”

Section: Discussionmentioning

confidence: 99%

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

et al. 2009

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DNA-hsp65, a DNA vaccine encoding the 65-kDa heat-shock protein of Mycobacterium leprae (Hsp65) is capable of inducing the reduction of established tumors in mouse models. We conducted a phase I clinical trial of DNA-hsp65 in patients with advanced head and neck carcinoma. In this article, we report on the vaccine's potential to induce immune responses to Hsp65 and to its human homologue, Hsp60, in these patients. Twenty-one patients with unresectable squamous cell carcinoma of the head and neck received three doses of 150, 400 or 600 mg naked DNA-hsp65 plasmid by ultrasound-guided intratumoral injection. Vaccination did not increase levels of circulating anti-hsp65 IgG or IgM antibody, or lead to detectable Hsp65-specific cell proliferation or interferon-g (IFN-g) production by blood mononuclear cells. Frequency of antigen-induced IL-10-producing cells increased after vaccination in 4 of 13 patients analyzed. Five patients showed disease stability or regression following immunization; however, we were unable to detect significant differences between these patients and those with disease progression using these parameters. There was also no increase in antibody or IFN-g responses to human Hsp60 in these patients. Our results suggest that although DNA-hsp65 was able to induce some degree of immunostimulation with no evidence of pathological autoimmunity, we were unable to differentiate between patients with different clinical outcomes based on the parameters measured. Future studies should focus on characterizing more reliable correlations between immune response parameters and clinical outcome that may be used as predictors of vaccine success in immunosuppressed individuals.

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Heat-shock proteins induce T-cell regulation of chronic inflammation

Cited by 491 publications

References 151 publications

The heat shock protein Hsp70 enhances antigen-specific proliferation of human CD4+ memory T cells

The heat shock protein Hsp70 enhances antigen-specific proliferation of human CD4+ memory T cells

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

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