Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

Gulko, Pércío S.

doi:10.1038/sj.gene.6364419

Cited by 9 publications

(5 citation statements)

References 124 publications

(97 reference statements)

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“…The studies reported here employed rat PIA since this T-cell dependent disease model mimics human RA, including symmetrical involvement of peripheral joints, destruction of cartilage and bone, dysregulated pro-inflammatory cytokines/chemokines, rheumatoid factor positivity, and its chronic course. PIA is dependent on MHC class II-restricted T-cells [ 26 ] and influenced by non-MHC genes, producing cellular and humoral autoimmunity [ 16 , 25 , 41 ]. Non-MHC genes that influence rat PIA arthritis severity include TNFα, IL-1β [ 42 ], IL-6, IL-17 [ 43 ], and CCL-2, and joint damaging MMPs [ 25 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

et al. 2017

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θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD-1 significantly reduced joint IL-1β levels compared with controls. RTD-1 dose-dependently inhibited fibroblast-like synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K. RTD-1 was non-toxic, non-immunogenic, and effective when administered as infrequently as once every five days. Thus θ-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA.

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Section: Discussionmentioning

confidence: 99%

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

et al. 2017

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“…For example, it is conceivable that some risk genes may interact with sex‐specific factors. They may also be specific for a single phenotype, and “susceptibility” genes may be less relevant than “severity” genes concerning the persistence of arthritis and joint‐destructive processes (14). We investigated whether APLEC influences autoimmunity in arthritis induced by rat type II collagen (CII), whether the genetic impact of APLEC is related to the way arthritis is triggered (i.e., to different types of arthritis), whether APLEC influences disease phenotypes other than susceptibility, and, finally, whether sex plays a role.…”

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confidence: 99%

Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen‐presenting lectin‐like receptor complex

Guo

Bäckdahl

Marta

et al. 2008

Arthritis & Rheumatism

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Objective. The antigen-presenting lectin-like receptor complex (APLEC) was recently identified as a genetic determinant for arthritis susceptibility. We undertook this study to define mechanisms underlying the impact of APLEC on arthritis, to determine whether sex effects occur, and to determine whether APLEC influences different types of arthritis and phenotypes other than susceptibility.Methods. Arthritis-susceptible DA rats were compared with sex-matched congenic rats in which APLEC alleles were substituted with alleles from arthritisresistant PVG rats. Six different arthritogenic agents were injected at the base of the tail: Freund's incomplete adjuvant, pristane, squalene, killed mycobacteria, yeast ␤-glucan, or rat type II collagen (CII). Arthritis was visually scored, body weight was measured, and anti-CII IgG and cytokine messenger RNA (mRNA) levels were determined by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction, respectively.Results. In 5 models of rheumatoid arthritis (RA), congenic rats deviated profoundly from DA rats by having reduced arthritis susceptibility, delayed onset, decreased severity, and/or reduced body weight loss. Paradoxical opposite genetic effects were noted, including a more severe disease course in congenic males in pristane-induced arthritis and decreased clinical signs in collagen-induced arthritis despite increased autoantibody levels. Interestingly, the anti-CII IgG isotype profile was skewed in congenic rats, and markedly reduced lymph node mRNA levels for interleukin-17 suggested that the cytokine profile of autoreactive T helper cells was also skewed in a less pathogenic direction.Conclusion. Rat APLEC regulates autoimmunity and multiple phenotypes in several types of arthritis. However, delineating the genetic impact may require stratification for sex or mode of arthritis induction. This pathogenetic complexity should be considered when evaluating APLEC in inflammatory and autoimmune diseases, including RA.

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“…The fibroblast-like synoviocyte (FLS) has a central role in the formation of the RA synovial pannus [5], and the in vitro invasive properties of FLS correlate with radiographic and histologic damage in RA [6] and in animal models of arthritis such as pristane-induced arthritis (PIA) [7]. Therefore, understanding the regulation of the invasive properties of FLS has the potential to generate new therapies aimed at reducing articular damage [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

The cation channel Trpv2 is a new suppressor of arthritis severity, joint damage, and synovial fibroblast invasion

Laragione

Cheng

Tanner

et al. 2015

Clinical Immunology

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Little is known about the regulation of arthritis severity and joint damage in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) have a central role in joint damage and express increased levels of the cation channel Trpv2. We aimed at determining the role of Trpv2 in arthritis. Treatment with Trpv2-specific agonists decreased the in vitro invasiveness of FLS from RA patients and arthritic rats and mice. Trpv2 stimulation suppressed IL-1β-induced expression of MMP-2 and MMP-3. Trpv2 agonists, including the new and more potent LER13, significantly reduced disease severity in KRN serum- and collagen-induced arthritis, and reduced histologic joint damage, synovial inflammation, and synovial blood vessel numbers suggesting anti-angiogenic activity. In this first in vivo use of Trpv2 agonists we discovered a new central role for Trpv2 in arthritis. These new compounds have the potential to become new therapies for RA and other diseases associated with inflammation, invasion and angiogenesis.

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Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

Cited by 9 publications

References 124 publications

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen‐presenting lectin‐like receptor complex

The cation channel Trpv2 is a new suppressor of arthritis severity, joint damage, and synovial fibroblast invasion

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