Altered susceptibility to collagen‐induced arthritis in transgenic mice with aberrant expression of interleukin‐1 receptor antagonist

Ma, Yuhe; Thornton, Sherry; Boivin, Gregory P.; Hirsh, David; Hirsch, Raphael; Hirsch, Emmet

doi:10.1002/1529-0131(199810)41:10<1798::aid-art11>3.3.co;2-c

Cited by 23 publications

(28 citation statements)

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“…Thus, administration of CII-I-A q -IgG3 to DBA/1 mice induced Ag-specific hyporesponsiveness. No inhibitory effects on anti-CII Ab titers was observed (data not shown), consistent with earlier observations that blocking T cell function can suppress CIA without affecting anti-CII Ab titers (11,37,43).…”

Section: In Vivo Administration Of Cii-i-a Q -Igg3 Induces Ag-specifisupporting

confidence: 92%

A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness

Zuo

Cullen

DeLay

et al. 2002

The Journal of Immunology

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T cells play a central role in many autoimmune diseases. A method to specifically target the function of autoreactive T cell clones would avoid the global immunosuppression associated with current therapies. To develop a molecule capable of inhibiting autoreactive T cell responses in vivo, single-chain peptide-I-A-IgG3 fusion proteins were constructed and expressed in both mammalian and insect cells. The fusion proteins were designed with an IgG3 Fc moiety to make them divalent, allowing TCR cross-linking, while lacking FcR binding and costimulation. The fusion proteins stimulated T cell hybridomas in vitro in a peptide-specific, MHC-restricted manner but failed to do so in soluble form. In vivo administration of an I-Aq fusion protein, containing an immunodominant collagen II peptide, significantly delayed the onset and reduced the severity of collagen-induced arthritis in DBA/1 mice by induction of Ag-specific hyporesponsiveness. Such fusion proteins may be useful to study novel therapeutic approaches for T cell-mediated autoimmune diseases.

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Section: In Vivo Administration Of Cii-i-a Q -Igg3 Induces Ag-specifisupporting

confidence: 92%

A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness

Zuo

Cullen

DeLay

et al. 2002

The Journal of Immunology

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“…Our hypothesis is further based on the observations that overexpression of IL-1ra in mice had significant reduction in the incidence and severity of collagen-induced arthritis. Furthermore, mice injected with neutralizing IL-1ra antibodies had a significantly earlier onset of collageninduced arthritis with increased inflammation and severity (36). Some of the beneficial effects of IL-1ra have been observed in humans, where infusion of IL-1ra significantly inhibited cartilage and bone damage (37).…”

Section: Discussionmentioning

confidence: 99%

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Attur¹,

Dave²,

Cipolletta³

et al. 2000

Journal of Biological Chemistry

119

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Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1␤-induced nitric oxide (NO) and/or prostaglandin E 2 production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC 50 for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1␤ mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance. Osteoarthritis (OA)1 is considered a non-inflammatory arthritis, characterized by a limited infiltration of neutrophils into the synovial space and, in general, an absence of the classical signs of inflammation. Chondrocytes embedded within articular cartilage that is avascular and aneural reside in a sequestered environment, perhaps more than other cell types, whereby cellular metabolism is regulated by an autocrine mechanism responsive to biomechanical and pericellular signals. Recent observations by this and other laboratories indicate that, despite the general absence of clinical signs of inflammation, chondrocytes derived from patients with OA, show superinduction of proinflammatory genes typically associated with the products of synovial tissues in rheumatoid arthritis, including nitric-oxide synthase, cyclooxygenase-2, TNF␣, IL-6, and IL-8. The spontaneous production of the corresponding gene products and inflammatory mediators promotes a catabolic state, which leads to progressive cartilage damage in OA (1-4). This intraarticular inflammatory response in OA-affected cartilage, which may be considered as an in situ "molecular inflammation," is partially dependent on autocrine IL-1␤ production, which induces and sustains an imbalance of cartilage homeostasis and extracellular matrix synthesis (5). The autocrine production of IL-1 in OA-affected cartilage is amplified by engagement of integrins such as ␣ 5 ␤ 1 by abnormally expressed extracellular matrix proteins, including proteolytic fragments of fibronectin (5, 6)...

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“…An imbalance between IL-1 and its naturally occurring inhibitor IL-1Ra may also predispose to inflammatory arthritis (18). Thus, the incidence and severity of CIA are significantly reduced in IL-1Ra transgenic mice and increased in IL-1Ra knockout mice (19).…”

Section: Tnf-α Il-1 and Il-1ra In Inflammatory Synovitismentioning

confidence: 99%

Cytokines and cellular interactions in inflammatory synovitis

Arend

2001

J. Clin. Invest.

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Altered susceptibility to collagen‐induced arthritis in transgenic mice with aberrant expression of interleukin‐1 receptor antagonist

Cited by 23 publications

References 0 publications

A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness

A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Cytokines and cellular interactions in inflammatory synovitis

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