Increased arthritis susceptibility in cartilage proteoglycan–specific T cell receptor–transgenic mice

Berlo, Suzanne E.; Guichelaar, Teun; Brink, Corlinda B. ten; Kooten, Peter J. S. van; Hauet-Broeren, Femke; Ludányi, Katalin; Eden, Willem van; Broeren, Chris P. M.; Glant, Tibor T.

doi:10.1002/art.22013

Cited by 41 publications

(80 citation statements)

References 48 publications

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“…Recently we have developed a new TCR-Tg mouse that expresses T cells specific for arthritis inducing human cartilage PG. 30 To explore the mechanism of immune regulation by antigen specific IL-10 producing T cell in an arthritis model in more depth, we have retrovirally transduced these PG specific cells with the murine IL-10 gene and green fluorescent protein (GFP) as selection marker. Transfer of these antigen specific IL-10+ cells not only suppressed the induction of arthritis in acceptor mice compared with cells transduced with GFP alone, but also induced IL-10 producing proteoglycan specific T cells within these mice, thereby spreading their regulatory function.…”

Section: Mechanismsmentioning

confidence: 99%

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

2005

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Section: Mechanismsmentioning

confidence: 99%

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

2005

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“…TCR-5/4E8-Tg BALB/c (PG-TCR Tg) mice (Berlo et al, 2006(Berlo et al, , 2005 and DO11.10 mice were bred and kept at the GDL under specific pathogen free conditions. Human PG (hPG) and were prepared as described elsewhere (Hanyecz et al, 2004).…”

Section: Mice and Antigensmentioning

confidence: 99%

“…Activity of IL-1RA was assessed using a NF-B-luciferase bioassay (Smeets et al, 2005). IL-4 and IL-10 were measured using fluoresceinated microspheres coated with ELISA capture antibodies (BD Pharmingen) as described elsewhere (Berlo et al, 2006) with a Luminex model 100 (Luminex, Austin, TX).…”

Section: Analysis Of Transgene Expressionmentioning

confidence: 99%

“…In addition to transduction with modulatory genes, PG-specific T cells were forced to differentiate into either T h 1 or T h 2 cells ex vivo in the presence of immune deviating cytokines and then transferred to test their impact on PGIA. Although PG-specific T cells are arthritogenic (Berlo et al, 2006(Berlo et al, , 2005Buzas et al, 1995) in lymphopenic hosts, naïve or T h 1 PG-specific T cells, as well as the other phenotypes that were tested, did not add to severity of arthritis when transferred in PGIA in wild type hosts. Surprisingly, most T cells expressing the different transgenes encoding well known immunosuppressive agents did not suppress arthritis.…”

Section: Introductionmentioning

confidence: 99%

“…The study presented here describes for the first time T-cell-based gene therapy with immunosuppressive proteins expressed by primary CD4 + T cells with a defined specificity for cartilage-derived antigen in a chronic model of RA. We transduced proteoglycan-specific CD4 + cells from a TCR-transgenic mouse (Berlo et al, 2006(Berlo et al, , 2005 with TNF-␣ receptor-Ig, IL-1 receptor antagonist, IL-4 or IL-10 and tested the immunomodulatory capacities of these CD4 + cells in cartilage proteoglycan-induced arthritis (PGIA). The progressive inflammation in PGIA is caused by T h 1 immunity (Finnegan et al, 1999;Hollo et al, 2000;Kaplan et al, 2002), depends on B cells (O'Neill et al, 2005) and bears similarities with clinical features and genetics of RA as reviewed in Glant et al (2003).…”

Section: Introductionmentioning

confidence: 99%

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Cartilage proteoglycan-specific T cells as vectors of immunomodulatory biologicals in chronic proteoglycan-induced arthritis

Guichelaar

Brink

Kooten

et al. 2008

Molecular Immunology

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a b s t r a c tSystemic administration of agents that neutralize or antagonize T h 1-mediated pro-inflammatory responses has been demonstrated to ameliorate inflammation in chronic autoimmune disease. However, systemic administration of such immunosuppressive biologicals causes serious side effects and has only limited success. To minimize these side effects, autoantigen-specific lymphocytes have been proposed as a carrier to deliver immunosuppressive agents to sites of inflammation. Here we studied the effects of primary cartilage proteoglycan-specific CD4 + T cells that were transduced using an efficient method of viral transduction with active genes encoding IL-1␤ receptor antagonist, soluble TNF-␣ receptor-Ig, IL-4 or IL-10 in chronic proteoglycan-induced arthritis in mice. This is the first study describing such gene therapy using primary CD4 + T cells in a chronic arthritis. Moreover, the impact of proteoglycan-specific T h 1, T h 2 or naïve T cells was studied. Although proteoglycan-TCR transgenic CD4 + T cells can transfer arthritis to lymphopenic recipients, none of the proteoglycan-TCR transgenic T cell phenotypes that were tested induced worsening of arthritis in wild type hosts. Proteoglycan-specific T cells ameliorated arthritis when expressing the transduced IL-10 gene, and not when expressing the other transgenes/phenotypes. Although all of the tested biologicals can suppress in a wide range of different inflammatory disorders, especially IL-10 would therefore serve as a promising candidate to be used in cellular gene therapy for chronic arthritis.

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Impaired activation‐induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan)–specific T cell receptor–transgenic mice

Boldizsár¹,

Kis-Tóth²,

Tarjányi³

et al. 2010

Arthritis & Rheumatism

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Objective. To investigate whether genetic preponderance of a T cell receptor (TCR) recognizing an arthritogenic peptide of human cartilage proteoglycan (PG) is sufficient for development of arthritis.Methods. We performed a longitudinal study using BALB/c mice expressing a TCR that recognizes the arthritogenic ATEGRVRVNSAYQDK peptide of human cartilage PG. PG-specific TCR-transgenic (PG-TCRTg) mice were inspected weekly for peripheral arthritis until 12 months of age. Peripheral joints were examined histologically, and T cell responses, T cell activation markers, serum cytokines, and autoantibodies were measured. Apoptosis and signaling studies were performed in vitro on T cells from aged PG-TCR-Tg mice.Results. Spontaneous arthritis developed as early as 5-6 months of age, and the incidence increased to 40-50% by 12 months of age. Progressive inflammation began with cartilage and bone erosions in the interphalangeal joints, and later expanded to the proximal joints of the front and hind paws. Spontaneous arthritis was associated with a high proportion of activated CD4؉ T cells, enhanced interferon-␥ and interleukin-17 (IL-17) production, and elevated levels of serum autoantibodies.PG-TCR-Tg mice lacking IL-4 developed arthritis earlier and at a higher incidence than IL-4-sufficient mice. Antigen-specific activation-induced cell death was diminished in vitro in CD4؉ T cells of PG-TCR-Tg mice with spontaneous arthritis, especially in those lacking IL-4.Conclusion. The presence of CD4؉ T cells expressing a TCR specific for an arthritogenic PG epitope is sufficient to trigger spontaneous autoimmune inflammation in the joints of BALB/c mice. IL-4 appears to be a negative regulator of this disease, through attenuation of activation-induced cell death.

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Increased arthritis susceptibility in cartilage proteoglycan–specific T cell receptor–transgenic mice

Cited by 41 publications

References 48 publications

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

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

Cartilage proteoglycan-specific T cells as vectors of immunomodulatory biologicals in chronic proteoglycan-induced arthritis

Impaired activation‐induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan)–specific T cell receptor–transgenic mice

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