CTLA4-Ig interferes and downregulates the proinflammatory activities of rheumatoid synovial macrophages in monoculture

Brizzolara, R.; Soldano, Stefano; Montagna, Paola; Sulli, Alberto; Seriolo, Bruno; Villaggio, Barbara; Triolo, Pierfranco; Clerico, Paolo; Felli, Lamberto; Molfetta, Luigi; Cutolo, Maurizio

doi:10.4081/reumatismo.2011.80

Cited by 7 publications

(7 citation statements)

References 12 publications

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“…Abatacept could also have an effect on osteoclast precursors, explaining the anti-erosive effects of abatacept [ 34 , 35 ], or on monocytes by modulating their migratory capacity [ 36 ]. Direct effects on macrophages have also been described resulting in decreased cytokine production and reduction of the inflammatory reaction [ 37 – 40 ], which could account for the beneficial effects in the treatment of RA.…”

Section: Discussionmentioning

confidence: 99%

Abatacept decreases disease activity in the absence of CD4+ T cells in a collagen-induced arthritis model

et al. 2015

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IntroductionAbatacept is a fusion protein of human cytotoxic T-lymphocyte–associated protein (CTLA)-4 and the Fc portion of human immunoglobulin G1 (IgG1). It is believed to be effective in the treatment of rheumatoid arthritis by inhibiting costimulation of T cells via blocking CD28–B7 interactions as CTLA-4 binds to both B7.1 (CD80) and B7.2 (CD86). However, the interaction of CD28 with B7 molecules is crucial for activation of naive cells, whereas it is unclear whether the action of already activated CD4+ T cells, which are readily present in established disease, also depends on this interaction. The aim of this study was to determine whether the mode of action of abatacept depends solely on its ability to halt T cell activation in established disease.MethodsArthritis was induced in thymectomized male DBA/1 mice by immunisation with bovine collagen type II. The mice were subsequently depleted for CD4+ T cells. Abatacept or control treatment was started when 80 % of the mice showed signs of arthritis. Arthritis severity was monitored by clinical scoring of the paws, and anti-collagen antibody levels over time were determined by enzyme-linked immunosorbent assay.ResultsTreatment with abatacept in the absence of CD4+ T cells resulted in lower disease activity. This was associated with decreasing levels of collagen-specific IgG1 and IgG2a antibodies, whereas the antibody levels in control or CD4+ T cell–depleted mice increased over time.ConclusionsThese results show that abatacept decreased disease activity in the absence of CD4+ T cells, indicating that the mode of action of abatacept in established arthritis does not depend entirely on its effects on CD4+ T cell activation.

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Section: Discussionmentioning

confidence: 99%

Abatacept decreases disease activity in the absence of CD4+ T cells in a collagen-induced arthritis model

et al. 2015

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“…Yet, how they influence these expressions appears to differ between RASF and EC. Our recent data showed that CTLA4-Ig (abatacept), by interacting with the CD86 molecule on RA synovial macrophages, may induce reverse signaling with anti-inflammatory effects, involving NFkB intracellular pathway [1][2][3][4]. Objectives: We investigated the expression and production of TNFalpha on cultured human activated macrophages before and after in vitro CTLA4-Ig treatment.…”

Section: Discussionmentioning

confidence: 99%

FRI0030 Anti-TNF-α Antibody Targeted To Inflamed Synovial Tissue for The Treatment of Rheumatoid Arthritis

Colombo

Sblattero

Maso

et al. 2016

Annals of the Rheumatic Diseases

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BackgroundTNF-α neutralizing molecules represent one of the most efficient therapeutic approaches to control inflammation in rheumatoid arthritis (RA). The widespread distribution in the body induces the inhibition of TNF-α in all the tissues, requesting the use of high dose of this expensive drug. Another problem that has not yet been solved in the management of RA patients is how to reduce and possibly avoid the side effects, particularly the increased risk of common and opportunistic infections, which may be associated with long-term administration of these therapeutic drugs.ObjectivesThe aim of the present investigation was to show that a recombinant protein obtained by fusing a synovial targeting peptide to an anti-TNF-α neutralizing antibody has a distinctive homing property for inflamed synovium and is effective in controlling joint inflammation in experimental models of arthritis.MethodsThe modified anti-TNF-α antibody specific for the synovial tissue (MC13) was generated by cloning the sequence for a synovial homing peptide (CKSTHDRLC) downstream of the cDNA for the variable regions of anti- TNF-α antibody adalimumab in the context of a miniantibody (scFv-Hinge-CH2-CH3 domains).Immunofluorescence technique was used to initially assess the ability of fluorescent-MC13 to target only inflamed synovial tissue. The biodistribution and the efficacy of the treatment with MC13 were evaluated in a rat model of antigen-induced arthritis (AIA).ResultsIn vitro studies have shown that adalimumab and MC13 maintain the ability to neutralize human TNF-α and bind to rat and mouse TNF-α. Based on these findings, we used a rat model of arthritis to evaluate their in vivo therapeutic effect. The ability of MC13 to selectively target inflamed synovial tissues was evaluated by immunofluorescence analysis. A rat model of antigen-induced mono-arthritis was used to analyse the in vivo distribution of MC13 labelled with the near-infrared probe cyanine 5.5 using time-domain near infrared optical imaging. The results showed that the labeled-MC13 preferentially localized in the inflamed synovium with a peak at 4 days and persisted for more than 3 weeks, while failing to bind to healthy synovial tissue.MC13 was able to prevent inflammation in the rat model of antigen-induced arthritis, as evaluated by the measurement of joint swelling, the count of PMN number and the level of IL6 in synovial tissue and the histologic assessment of tissue damage.Intravenous injection of MC13 prevents acute inflammation in all the animals while the same dose of adalimumab was almost ineffective. MC13, administred i.v. 4 days after arthritis induction, was also able to cure joints analysed 7 days after the induction of inflammation.ConclusionsOur results demonstrated that MC13 can selectively target inflamed and abrogate the inflammation in a model of antigen-induced arthritis with no sign of toxicity.Disclosure of InterestNone declared

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“…In support of this, increased levels of osteoclast precursors were found in untreated patients with RA compared to healthy donors and these levels normalized following treatment with CTLA‐4/Ig therapy . The migratory capacity of monocytes and ability of synovial macrophages to produce inflammatory cytokines in vitro were also attenuated by CTLA‐4/Ig . A direct role in for anti‐CTLA‐4 therapy in promoting joint damage is further strengthened by the finding that the levels of circulating osteoclast precursors and potential to form osteoclasts increased in patients receiving anti‐CTLA‐4 treatment (ipilimumab) for the treatment of melanoma.…”

Section: Immune Checkpoints In Iamentioning

confidence: 99%

“…13 The migratory capacity of monocytes and ability of synovial macrophages to produce inflammatory cytokines in vitro were also attenuated by CTLA-4/Ig. [17][18][19] A direct role in for anti-CTLA-4 therapy in promoting joint damage 17 is further strengthened by the finding that the levels of circulating osteoclast precursors and potential to form osteoclasts increased in patients receiving anti-CTLA-4 treatment (ipilimumab) for the treatment of melanoma. Together, these data support a mechanism where CTLA-4 blockade may promote the development of ICI-IA through two mechanisms: (a) the reactivation of autoreactive joint-specific T cells; and (b) direct effects on monocytes that promote the production of inflammatory cytokines, extravasation into tissues, and differentiation into osteoclasts.…”

Section: Ctla-4 Checkpointmentioning

confidence: 99%

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

Cappelli¹,

Thomas²,

Bingham³

et al. 2020

Immunological Reviews

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The development of inflammatory arthritis in patients receiving immune checkpoint inhibitor therapy is increasingly recognized due to the growing use of these drugs for the treatment of cancer. This represents an important opportunity not only to define the mechanisms responsible for the development of this immune‐related adverse event and to ultimately predict or prevent its development, but also to provide a unique window into early events in the development of inflammatory arthritis. Knowledge gained through the study of this patient population, for which the inciting event is known, could shed light into the pathogenesis of autoimmune arthritis. This review will highlight the clinical and immunologic features of these entities to define common elements for future study.

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CTLA4-Ig interferes and downregulates the proinflammatory activities of rheumatoid synovial macrophages in monoculture

Cited by 7 publications

References 12 publications

Abatacept decreases disease activity in the absence of CD4+ T cells in a collagen-induced arthritis model

Abatacept decreases disease activity in the absence of CD4+ T cells in a collagen-induced arthritis model

FRI0030 Anti-TNF-α Antibody Targeted To Inflamed Synovial Tissue for The Treatment of Rheumatoid Arthritis

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

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