CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody-positive rheumatoid arthritis patients

Pieper, Jennifer; Herrath, Jessica; Raghavan, Sukanya; Muhammad, Khalid; Vollenhoven, Ronald van; Malmström, Vivianne

doi:10.1186/1471-2172-14-34

Cited by 87 publications

(79 citation statements)

References 32 publications

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“…The underlying reason for the observed differences in response for ABA and TNFi is unknown, but may be related to differences in the mechanism of action between treatments. The association between seropositivity and ABA response could be due to the upstream mechanism of action of ABA, by which costimulation blockade inhibits Th cell activation and subsequently modulates B cells and autoantibody production 11,12 . Anti-CCP is associated with erosive disease 5 , and therefore it is important to have a reliable biomarker to help identify patients who will benefit from treatment response.…”

Section: Rheumatologymentioning

confidence: 99%

Effect of Anticitrullinated Protein Antibody Status on Response to Abatacept or Antitumor Necrosis Factor-α Therapy in Patients with Rheumatoid Arthritis: A US National Observational Study

Harrold

Litman²,

Connolly³

et al. 2017

J Rheumatol

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Objective.Assess whether baseline anticyclic citrullinated peptide antibodies (anti-CCP) status is associated with treatment response in patients with rheumatoid arthritis (RA) initiating abatacept (ABA) or a tumor necrosis factor-α inhibitor (TNFi).Methods.Using the Corrona RA registry, patients were identified who initiated ABA or a TNFi (June 2004–January 2015), had a followup visit 6 months (± 3 mos) after initiation, and anti-CCP measured at or prior to initiation. Primary outcome was mean change in Clinical Disease Activity Index (CDAI) from initiation to 6 months. Treatment response was evaluated based on a typical patient profile (female, aged 57 yrs, body mass index of 30 kg/m2, baseline CDAI of 20, 1 prior biologic, and no comorbidities other than RA). Secondary outcomes included remission and low disease activity.Results.There were 566 ABA initiators [anti-CCP+ (≥ 20 units/ml): n = 362; anti-CCP− (< 20 units/ml): n = 204] and 1715 TNFi initiators (anti-CCP+: n = 1113; anti-CCP−: n = 602). Differences between treatment groups included baseline disease duration, CDAI, and prior biologic use. At 6 months, anti-CCP+ ABA initiators were associated with significantly greater CDAI response versus anti-CCP− ABA initiators; no significant difference was observed for TNFi initiators. When considering a typical RA patient profile, CDAI response was greater in anti-CCP+ versus anti-CCP− ABA initiators; anti-CCP+ versus anti-CCP− TNFi initiators were similar. Secondary outcome responses were also greater in anti-CCP+ versus anti-CCP− ABA initiators; TNFi initiators did not differ by anti-CCP status.Conclusion.In a US-based clinical practice setting, anti-CCP status was associated with a differential treatment response to ABA, but not TNFi.

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Section: Rheumatologymentioning

confidence: 99%

Effect of Anticitrullinated Protein Antibody Status on Response to Abatacept or Antitumor Necrosis Factor-α Therapy in Patients with Rheumatoid Arthritis: A US National Observational Study

Harrold

Litman²,

Connolly³

et al. 2017

J Rheumatol

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“…However, know-how on the molecular details underlying the effects observed is likely of relevance as these effects may have important implications for therapies aiming to block costimulatory pathways such as employed in autoimmune diseases. Although CTLA4-Ig is being successfully used as treatment for a variety of autoimmune diseases, it does not completely inhibit T-cell activation, suggesting that CD28-independent pathways may contribute to autoreactive T-cell responses as well [11,[21][22][23]. Our results suggest that this treatment may not inhibit mast cell mediated-, and possibly other forms of T-cell activation.…”

mentioning

confidence: 66%

Human mast cells costimulate T cells through a CD28‐independent interaction

et al. 2016

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Mast cells are innate immune cells usually residing in peripheral tissues, where they are likely to activate T-cell responses. Similar to other myeloid immune cells, mast cells can function as antigen-presenting cells. However, little is known about the capacity of human mast cells to costimulate CD4 + T cells. Here, we studied the T-cell stimulatory potential of human mast cells. Peripheral blood derived mast cells were generated and cocultured with isolated CD4 + T cells. In the presence of T-cell receptor triggering using anti-CD3, mast cells promoted strong proliferation of T cells, which was two-to fivefold stronger than the "T-cell promoting capacity" of monocytes. The interplay between mast cells and T cells was dependent on cell-cell contact, suggesting that costimulatory molecules on the mast cell surface are responsible for the effect. However, in contrast to monocytes, the T-cell costimulation by mast cells was independent of the classical costimulatory molecule CD28, or that of OX40L, ICOSL, or LIGHT. Our data show that mast cells can costimulate human CD4 + T cells to induce strong T-cell proliferation, but that therapies aiming at disrupting the interaction of CD28 and B7 molecules do not inhibit mast cell mediated T-cell activation. Additional supporting information may be found in the online version of this article at the publisher's web-site Keywords IntroductionMast cells are innate immune cells derived from myeloid progenitors. They have been originally described as one of the effector cells in allergic IgE-mediated responses. More recently, their role in immune regulation, and specifically in regulation of adaptive immune responses, has been recognized [1]. For example, we and others have shown that mast cells can function as antigenpresenting cells through cognate interactions with CD4 + T cells both in human and mouse [2][3][4]. CD4 + T-cell activation in this context was dependent on recognition of specific antigens in the Correspondence: Dr. René E. M. Toes e-mail: r.e.m.toes@lumc.nl context of MHC class II. Activation and skewing of T cells generally requires the presence of three signals, consisting of antigen presentation through MHC, costimulation, and specific cytokine signals [5]. Costimulation is the interaction of membrane-bound receptors on T cells and antigen-presenting cells that enhance signals through the T-cell receptor, and that is necessary to induce full T-cell activation, proliferation, and survival. Classical costimulation consists of CD28-mediated signaling by B7 family members on antigen-presenting cells, although different molecules, such as members of the TNF receptor superfamily or signaling lymphocyte activation molecule family are known to regulate the balance between T-cell death and survival as well [6].We have previously shown the presence of mast cells in T-cell areas of lymphoid organs [2], as well as their colocalization in synovial tissue [7], suggesting that mast cells could modulate [8,9]. This effect in the mouse was directly mediated through TNF produ...

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“…Indeed, abatacept was able to prevent antigen-presenting cells (APCs) from delivering CD28-dependent costimulatory signals to T cells [37]. Furthermore, abatacept has demonstrated longterm efficacy in various forms of rheumatoid arthritis [38,39], as well as other disease conditions [40,41].…”

Section: Journal Of Autoimmune Disorders Issn 2471-8513mentioning

confidence: 99%

Immune checkpoint-targeted therapy: cancer and autoimmune diseases represent two sides of the same coin

Isakov¹

2016

J Autoimmune Disord

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The immune system plays a critical role in tumor surveillance and cancer prevention. However, some cancer cells can evade immune destruction by acquiring the ability to inhibit immune checkpoint regulatory pathways and suppress anti-cancer immune responses. In recent years, the immune checkpoints took center stage in cancer immunotherapy and several promising strategies, based on the intervention in immune checkpointregulated pathways, have been designed in order to overcome mechanisms of immunosuppression. Clinical studies, using anti-inhibitory immune checkpoint-receptor antibodies, demonstrated durable clinical responses even in patients with advanced cancer. However, the clinical benefit was limited to a subset of cancer patients. Furthermore, the immune checkpoint therapy, which unleashes the immune system in order to augment the anti-cancer immune response, also increases the incidence of autoimmune diseases and induces an array of immune-related adverse effects. Here we briefly discuss some of the pros and cons of immune checkpoint-directed immunotherapy.

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CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody-positive rheumatoid arthritis patients

Cited by 87 publications

References 32 publications

Effect of Anticitrullinated Protein Antibody Status on Response to Abatacept or Antitumor Necrosis Factor-α Therapy in Patients with Rheumatoid Arthritis: A US National Observational Study

Effect of Anticitrullinated Protein Antibody Status on Response to Abatacept or Antitumor Necrosis Factor-α Therapy in Patients with Rheumatoid Arthritis: A US National Observational Study

Human mast cells costimulate T cells through a CD28‐independent interaction

Immune checkpoint-targeted therapy: cancer and autoimmune diseases represent two sides of the same coin

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