Tolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthritis

Kamphuis, Sylvia; Kuis, Wietse; Jager, Wilco de; Teklenburg, Gijs; Massa, Margherita; Gordon, Grace; Boerhof, Marjolein; Rijkers, Ger T.; Uiterwaal, Cuno S.P.M.; Otten, Henny G.; Sette, Alessandro; Albani, Salvatore; Prakken, Berent J.

doi:10.1016/s0140-6736(05)66827-4

Cited by 160 publications

(126 citation statements)

References 26 publications

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“…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]. Possible Hsp60 T cell epitopes were recently identified [39]. However, the induction of regulatory T cell responses by T cells reactive to self-Hsp has to be distinguished from the enhanced reactivity to peptides chaperoned by HSP as shown in these experiments.…”

Section: Discussionmentioning

confidence: 79%

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: 79%

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

et al. 2005

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“…As described above, the peptides were identified by their theoretical capacity to bind to multiple HLA-DR molecules. Their pan-DR-binding capacity was also confirmed by in vitro MHC binding assays (31). To further confirm that the documented proliferative response of PBMCs from RA patients to the novel epitopes was indeed HLA-DR dependent, we performed lymphocyte stimulation assays in the presence of blocking anti-HLA-DR antibodies.…”

Section: De Jong Et Almentioning

confidence: 77%

“…PBMCs from 20 randomly selected RA patients (see Table 1 for demographic and clinical characteristics) were tested for their proliferative response (using 3 H-thymidine incorporation) to the peptide pairs of peptides p1-p8 (Table 2). Based on observations published earlier, an SI that is twice that of the background value is defined as a positive proliferative response (31,39). The proliferative response obtained without adding the antigen (defined as the background value) ranged from 170 cpm to 1,000 cpm (mean 395 cpm).…”

Section: Resultsmentioning

confidence: 99%

“…The sequential use of a combined DR1/DR4/DR7 algorithm can be used to identify broadly crossreactive DR-binding peptides (34). In vitro major histocompatibility complex (MHC) binding studies have confirmed that Hsp60 peptides identified by the computer algorithm were indeed able to bind to a diverse range of HLA-DR molecules (31). The pan-DR-binding peptides were synthesized by automated, simultaneous, multiple-peptide synthesis, with a purity Ͼ95%, as described previously (35).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we identified pan-DR-binding epitopes of both the human and the mycobacterial Hsp60 protein (31,32). The goal of this study was to characterize the disease specificity and function of these Hsp60-derived epitopes as contributors to the modulation of an autoimmune inflammatory loop that may be self-reverberating in a manner independent of its trigger.…”

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confidence: 99%

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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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HSP60 Speaks to the Immune System in Many Voices

Quintana

Cohen

2008

Novartis Foundation Symposia

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Tolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthritis

Cited by 160 publications

References 26 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

HSP60 Speaks to the Immune System in Many Voices

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