Immune regulation in adjuvant‐induced arthritis: Possible implications for innovative therapeutic strategies in arthritis

Eden, Willem van; Waksman, Byron H.

doi:10.1002/art.11077

Cited by 33 publications

(25 citation statements)

References 81 publications

(67 reference statements)

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“…We believe that the peptide studied here is part of a pool of antigens that share characteristics such as their availability at the site of inflammation, strong proinflammatory effect on T cell responses in RA and, in certain instances, interspecies homologies (40). Peptides derived from heat shock protein fulfill this profile.…”

Section: Resultsmentioning

confidence: 87%

Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis

Prakken

Samodal

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

202

157

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Modulation of epitope-specific immune responses would represent a major addition to available therapeutic options for many autoimmune diseases. The objective of this work was to induce immune deviation by mucosal peptide-specific immunotherapy in rheumatoid arthritis (RA) patients, and to dissect the related immunological mechanisms by using a technology for the detection of low-affinity class II-restricted peptide-specific T cells. A group of patients with early RA was treated for 6 months orally with dnaJP1, a peptide that induces proinflammatory T cell responses in naive RA patients. Immunological analysis at initial, intermediate and end treatment points showed an intriguing change from proinflammatory to regulatory T cell function. In fact, dnaJP1-induced T cell production of IL-4 and IL-10 increased significantly when initial and end treatment points were compared, whereas dnaJP1-induced T cell proliferation and production of IL-2, IFN-␥, and tumor necrosis factor-␣ decreased significantly. The total number of dnaJP1-specific cells did not change over time, whereas expression of foxP3 by CD4 ؉ CD25 bright cells increased, suggesting that the treatment affected regulatory T cell function. Thus, rather than clonal deletion, the observed change in immune reactivity to dnaJP1 was the outcome of treatment-induced emergence of T cells with a different functional phenotype. This study contributes to our knowledge of mechanisms and tools needed for antigen-specific immune modulation in humans, thus laying the foundation for exploitation of this approach for therapeutic purposes.

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Section: Resultsmentioning

confidence: 87%

Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis

Prakken

Samodal

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

202

157

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“…First, experiments in the adjuvantinduced arthritis model suggest that Hsp60 might play a crucial role in the immune regulation of arthritis (25). Second, in RA, as well as in juvenile idiopathic arthritis (JIA), Hsp60 of microbial origins as well as those of endogenous origins are targets of immune responses (26,27).…”

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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“…In this study, we have examined the kinetics, the Ag/epitope specificity, and the functional attribute of Abs directed against the disease-related Ags in the rat adjuvant-induced arthritis (AA) model of human RA (18,19). AA is inducible in Lewis rats (RT.1 l ) by s.c. immunization with heat-killed Mycobacterium tuberculosis H37Ra (Mtb) (18), and T cells directed against mycobacterial heat shock protein (hsp) 65 (Bhsp65) are believed to play a pivotal role in disease induction (20).…”

mentioning

confidence: 99%

Antibody Responses to Mycobacterial and Self Heat Shock Protein 65 in Autoimmune Arthritis: Epitope Specificity and Implication in Pathogenesis

Kim

Černý

et al. 2006

The Journal of Immunology

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Many autoimmune diseases are believed to involve primarily T cell-mediated effector mechanisms. There is increasing realization, however, that Abs may also play a vital role in the propagation of T cell-driven disorders. In this study, on the rat adjuvant-induced arthritis (AA) model of human rheumatoid arthritis, we examined the characteristics of serum Ab response to mycobacterial heat shock protein (hsp) 65 (Bhsp65), self (rat) hsp65 (Rhsp65), and linear peptides spanning these two molecules. The AA-resistant WKY (RT.1l) rat responded to the heat-killed Mycobacterium tuberculosis immunization with a rapid burst of Abs to both Bhsp65 and Rhsp65. These Abs reacted with numerous peptide epitopes; however, this response was reduced to a few epitopes with time. On the contrary, the susceptible Lewis (RT.1l) rat developed a relatively lower Ab response to Bhsp65, and Abs to Rhsp65 did not appear until the recovery from the disease. The Ab response in Lewis rats diversified with progression of AA, and there was an intriguing overlap between the repertoire of Bhsp65-reactive B and T cells during the recovery phase of AA. Nonetheless, subsets of the repertoire of the late Abs in both rat strains became focused on the same epitope regions of Bhsp65 and Rhsp65. The functional relevance of these Abs was evident from the results showing that sera from recovery phase Lewis or WKY rats, but not that of naive rats, afforded protection against subsequent AA. These results are of significance in further understanding of the role of humoral immunity in the pathogenesis of autoimmune arthritis.

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Immune regulation in adjuvant‐induced arthritis: Possible implications for innovative therapeutic strategies in arthritis

Cited by 33 publications

References 81 publications

Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis

Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis

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

Antibody Responses to Mycobacterial and Self Heat Shock Protein 65 in Autoimmune Arthritis: Epitope Specificity and Implication in Pathogenesis

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