Review
Advances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis

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Abstract

Rheumatoid arthritis (RA) is a multifactorial and polygenic immune-mediated disease, the pathogenesis of which involves different cell types. T and B lymphocytes, macrophages, endothelial cells, fibroblasts and osteoclasts have all been implicated in mediating the production of autoantibodies, proinflammatory cytokines and ultimately bone erosions. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4-Ig, abatacept) is a unique biologic agent targeting the co-stimulatory molecules CD80/CD86, and is indicated for the treatment of moderate-to-severe RA in patients who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs, including methotrexate or anti-tumor necrosis factor agents. There is a growing body of evidence that, through selective modulation of the CD80/CD86 co-stimulatory molecules expressed by a variety of activated cell types, CTLA-4-Ig may inhibit the pathogenic RA process at several levels, both directly and indirectly. Here, we provide an overview of recent mechanistic studies of the action of CTLA-4-Ig on different cell types involved in mediating inflammation and joint damage in RA.

Introduction

Rheumatoid arthritis (RA) is a polygenic, multifactorial and chronic, immune-mediated disease. It is characterized by systemic, chronic joint inflammation that leads to structural damage, as well as by extra-articular involvement. The immunopathology of RA is complex, and involves different cell types. However, despite much research and many advances in recent years, the complete mechanism of disease remains to be fully elucidated [1]. Some possible arthritogenic antigens (including citrullinated antigens) thought to trigger the T cell-initiated inflammatory response characteristic of the RA disease process are the subject of continued research [2], [3]. T-cell interaction with B cells leads to increased production of autoantibodies – rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP) – that are implicated in the early progression of the disease. A number of polymorphisms associated with RA are involved in T-cell activation, providing additional support for the role of T cells in this disease [4]. The T cell-initiated immune cascade leads to increased migration and proliferation of inflammatory cells, such as macrophages, monocytes, leukocytes and fibroblast-like synoviocytes, which infiltrate the synovial tissue [1]. Activation of these cell types leads to increased production of proinflammatory cytokines (such as anti-tumor necrosis factor [TNF]-α, interleukin [IL]-1, IL-6 and IL-17), and local growth factors, which contribute to joint swelling and pain [1]. The presence of proinflammatory cytokines and local vascular growth factors in the synovial tissue leads to activation of endothelial cells, which subsequently express adhesion molecules that further promote the recruitment of inflammatory cells into the joint as well as induce angiogenesis [5]. In addition to increased production of proinflammatory cytokines, activated macrophages and osteoclasts secrete metalloproteinases, which are responsible for bone and cartilage degradation [1]. Inflammatory cytokines and the receptor activator of nuclear factor-κ B ligand (RANKL) stimulate the development of osteoclasts, which also produce metalloproteinases that subsequently exert an effect on structural damage [1]. Interestingly, in pre-RA, anti-citrullinated protein antibody-positive individuals show signs of periarticular bone damage even before the clinical phase of RA has started, demonstrating that autoimmunity is complicated by bone loss [6].

Treatment of early RA conventionally starts with non-biologic disease-modifying anti-rheumatic drugs (DMARDs), namely methotrexate (MTX) or leflunomide, which are the gold standard. Patients with established RA who have had an inadequate response to MTX may integrate their therapy with other drugs such as biologic DMARDs [7], [8], [9]. Biologics can target a variety of cytokines that are involved in the inflammatory cascade, such as TNF-α and IL-6, whereas some can also target CD20 + B cells, leading to their depletion, or can modulate T-cell co-stimulation and activation (Fig. 1). Newer biologics are being developed that target intracellular JAK/STAT and MAPK signaling pathways involved in the immune cascade (Fig. 1) [10]. Biologics with different mechanisms of action may exert different clinical effects on early and established disease, depending on which cell types they influence; they may also have different clinical effects depending on patient disease characteristics and underlying disease pathology. In fact, two different and prevalent populations of patients with RA can be characterized by predominantly T (75%) or B (25%) lymphocyte-driven activation of inflammation [11].

As we understand more about the pathways involved in the inflammatory process, additional therapeutic targets emerge for the immunopathologic responses involved in RA. One such therapeutic target is the CD28:CD80/86 (B7.1/B7.2) co-stimulatory pathway, which has a key role in the full activation of T cells [12] and in determining the fate of immune/inflammatory responses. The co-stimulatory molecules expressed by activated T cells represent a unique target for biologic therapy in RA. As such, the cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4-Ig) that selectively modulates the CD28:CD80/86 (B7.1/B7.2) co-stimulation signal (abatacept, Bristol-Myers Squibb, NJ, United States) is one biologic DMARD that is indicated for use in patients with active RA and an inadequate response to other DMARDs (including MTX or anti-TNF). There are various forms of CTLA-4-Ig, including a murine version of CTLA-4-Ig, human CTLA-4-Ig (which does not contain the modified Fc domain described in Section 2) and abatacept. Herein, we refer to these various forms as CTLA-4-Ig; however, all the clinical studies discussed utilized abatacept.

CTLA-4-Ig works early in the inflammatory response – at the point of naïve T-cell activation – and impacts cells involved early in the disease process — both T and B cells. It has proven clinical and radiographic efficacy in the treatment of RA and is well tolerated, with low immunogenicity [13], [14], [15], [16], [17], but the mechanisms underlying its efficacy and tolerability remain to be fully elucidated. The objective of this article is to review and provide an expert opinion on recent publications that have contributed to a wider understanding of the consequences of CTLA-4-Ig-mediated co-stimulation modulation, with an emphasis on mechanistic studies of its action on various cell types involved in mediating inflammation and joint damage in RA. Recent publications relevant to the mechanism of action of CTLA-4-Ig in RA, as identified by the authors from their own expertise and knowledge, were included. PubMed searches were conducted using the following search terms to identify additional papers of potential interest that had been published since 2009: “(Abatacept OR CTLA-4-Ig) AND rheumatoid arthritis” in combination with each of the following: (CD80 OR CD86), (co-stimulation modulation OR co-stimulation modulation), T cell, B cell, lymphocyte, macrophage, osteoclast, regulatory T cell (Treg) and endothelial cell.

Section snippets

Selective modulation of T-cell co-stimulation by CTLA-4-Ig: an overview

The T-cell immune response is triggered by presentation of an antigen by antigen-presenting cells (APC) via a trimolecular complex comprising major histocompatibility complex (MHC) on the APC, the peptide antigen that has triggered the immune response, and the T-cell membrane receptor (TCR) specific for that antigen [18]. However, antigen presentation alone is not sufficient to drive T-cell activation; an additional, regulated signal between the APC and naïve T lymphocyte is required. The

The wider consequences of CTLA-4-Ig-mediated co-stimulation modulation: furthering our understanding

Research over many years has shown that, in addition to T cells, a number of other cell types play a role in the pathogenesis of RA. B lymphocytes, macrophages, endothelial cells and osteoclasts are implicated in mediating the production of autoantibodies, proinflammatory cytokines and proteinases, and ultimately bone erosion. There is a growing body of evidence that, through selective modulation of the CD28 co-stimulatory pathway or through binding to CD80 and CD86, CTLA-4-Ig may target these

Discussion

It is well established that CTLA-4-Ig competes with CD28 for binding to CD80 and CD86 receptors on APCs, modulating the co-stimulatory signal required for full T-cell activation early in the inflammatory cascade [12], [21]. Recent studies overviewed here reveal that CTLA-4-Ig also impacts different T- and B-cell types involved in RA disease processes and pathology [31], [32], [33], [34], [35], [36], [47], [48], and may be involved in directly downregulating cytokine production by macrophages

Disclosure statement

M. Cutolo has received financial support from Bristol-Myers Squibb for laboratory research (funds to the University). S. Nadler is an employee of Bristol-Myers Squibb.

Take-home messages

  • CTLA-4-Ig is a biologic (abatacept) used for the treatment of RA and, in initial studies, was found to selectively modulate T-cell activation by binding to the co-stimulatory molecules CD80/CD86. Overall, data suggest that CTLA-4-Ig has a unique mechanism of action involving broad but targeted immunomodulatory effects, which result in a global dampening of a variety of immune mechanisms involved in RA.

  • Through direct interactions with the co-stimulatory molecules CD80/CD86 on other cells,

Acknowledgments

Professional medical writing and editorial assistance was provided by Eve Guichard, BSc (Hons), and MaiLee Wong, PhD, of Caudex Medical and funded by Bristol-Myers Squibb.

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