Targeting the inflamed synovium: The quest for specificity

Garrood, Toby; Pitzalis, Costantino

doi:10.1002/art.21720

Cited by 26 publications

(14 citation statements)

References 55 publications

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“…gene therapy) under investigation (3,4,8,9), most of them do not have arthrotropicity. Generally, this lack of tissue specificity combined with the ubiquitous distribution of the molecular targets may explain the significant systemic and extra-articular adverse events often associated with antirheumatic drugs (10,11). …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis

et al. 2008

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Purpose-To develop a pH-sensitive dexamethasone (Dex)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer conjugate with well-defined structure for the improved treatment of rheumatoid arthritis (RA).Methods-A new pH-sensitive Dex-containing monomer (MA-Gly-Gly-NHN=Dex) was synthesized and copolymerized with HPMA using reversible addition-fragmentation transfer (RAFT) polymerization. The structure of the resulting HPMA copolymer-Dex conjugate (P-Dex) was analyzed and its therapeutic efficacy was evaluated on adjuvant-induced arthritis (AIA) rats.Results-P-Dex was synthesized with controllable molecular weight and polydispersity index (PDI). The Dex content can be controlled by the feed-in ratio of MA-Gly-Gly-NHN=Dex. The PDex used for in vitro and in vivo evaluation has a weight average molecular weight (M w ) of 34 kDa and a PDI of 1.34. The in vitro drug-release studies showed that the Dex release from the conjugate was triggered by low pH. Clinical measurements, endpoint bone mineral density (BMD) test and histology grading from the in vivo evaluation all suggest that newly synthesized P-Dex has strong and long-lasting anti-inflammatory and joint protection effects.Conclusions-A HPMA copolymer-dexamethasone conjugate with a well-defined structure has been synthesized and proved to be an effective anti-arthritis therapy. It may have a unique clinical application in the treatment of rheumatoid arthritis.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis

et al. 2008

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“…Conceptually, therapeutic intervention focused on modulation of T cell function leads to the promise of higher specificity and lower toxicity[7]–[16]. This objective has for long remained a challenge in humans, particularly due to the difficulty of identifying means of intervention that could affect T cell function in a specific fashion.…”

Section: Introductionmentioning

confidence: 99%

Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis

Roord

Zonneveld‐Huijssoon

et al. 2006

PLoS ONE

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Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation.

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“…Molecular imaging techniques that use targeted agents binding specifically to inflamed synovium are increasingly allowing earlier diagnoses and assessment of a treatment response in RA (2-4). Several studies have shown that it is possible to target and visualize specific cellular processes in arthritic synovium using molecular imaging approaches (5-8).…”

mentioning

confidence: 99%

“…The vascular endothelium is an attractive target for imaging and therapy in RA due to its obvious accessibility through the systemic circulation (4-6, 9). The intercellular adhesion molecule (ICAM)-1 is primarily found on synovial endothelial cells and helps recruit lymphocytes, monocytes, and neutrophils to the joints in RA (10-12).…”

mentioning

confidence: 99%

Molecular MR Imaging for Visualizing ICAM-1 Expression in the Inflamed Synovium of Collagen-Induced Arthritic Mice

Lee

Yoon

et al. 2009

Korean J Radiol

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ObjectiveTo determine the utility of intercellular adhesion molecule (ICAM)-1 antibody-conjugated gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA-anti-ICAM-1) as a targeted contrast agent for the molecular magnetic resonance imaging (MRI) in collagen-induced arthritis (CIA).Materials and MethodsThree groups of mice were used: non-arthritic normal, CIA mice in both the early inflammatory and chronic destructive phases. The MR images of knee joints were obtained before and after injection of Gd-DTPA-anti-ICAM-1, Gd-DTPA, and Gd-DTPA-Immunoglobulin G (Ig G) and were analyzed quantitatively. The patterns of enhancement on the MR images were compared with the histological and immunohistochemical ICAM-1 staining.ResultsThe images obtained after injection of Gd-DTPA-anti-ICAM-1 displayed gradually increasing signal enhancement from the moment following injection (mean ± standard deviation [SD]: 424.3 ± 35.2, n = 3) to 24 hours (532 ± 11.3), rather than on pre-enhanced images (293 ± 37.6) in the early inflammatory phase of CIA mice. However, signal enhancement by Gd-DTPA and Gd-DTPA-IgG disappeared after 80 minutes and 24 hours, respectively. In addition, no significant enhancement was seen in the chronic destructive phase of CIA mice, even though they also showed inflammatory changes on T2-weighted MR images. ICAM-1 expression was demonstrated in the endothelium and proliferating synovium of the early inflammatory phase of CIA mice, but not in the chronic destructive phase.ConclusionMolecular MRI with Gd-DTPA-anti-ICAM-1 displays specific images targeted to ICAM-1 that is expressed in the inflamed synovium of CIA. This novel tool may be useful for the early diagnosis and differentiation of the various stages of rheumatoid arthritis.

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Targeting the inflamed synovium: The quest for specificity

Cited by 26 publications

References 55 publications

Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis

Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis

Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis

Molecular MR Imaging for Visualizing ICAM-1 Expression in the Inflamed Synovium of Collagen-Induced Arthritic Mice

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