Prophylactic administration of abatacept prevents disease and bone destruction in a rat model of collagen-induced arthritis
Introduction
Rheumatoid arthritis (RA) is a complex autoimmune disease affecting approximately 1% of the population [1]. The disease is characterized by synovial membrane hyperplasia and infiltration of inflammatory cells, including activated T cells [2]. T cells play a fundamental role in the initiation and perpetuation of RA immunopathology, leading to downstream inflammation and, ultimately, soft tissue and joint destruction. Following activation, T cells proliferate and stimulate monocytes, macrophages and synovial fibroblasts to produce pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6 [2]. Immunoglobulin (Ig) production by B cells [3], osteoclastogenesis, and matrix metalloproteinase (MMP) secretion [4] are also downstream of T-cell activation.
The central role of activated T cells in RA immunopathology makes T-cell activation a rational therapeutic target. One of the initial steps in T-cell activation is antigen recognition through the T-cell receptor. Following antigen recognition, T cells require a co-stimulatory signal for full activation, one of the best characterized being engagement of CD80/86 on antigen presenting cells (APCs) with CD28 on T cells [5]. In the normal immune response, expression of endogenous cytotoxic T lymphocyte-associated antigen-4 (CTLA4) is then induced, which, in turn, downregulates CD28-mediated T-cell activation by binding to CD80/86 with greater affinity than CD28 [6].
Abatacept (CTLA4-Ig) is a soluble recombinant human fusion protein comprising the extracellular domain of human CTLA4 and a fragment of the Fc domain of human IgG1. The first in a new class of agents, abatacept modulates T-cell activation by interfering with the engagement of CD80/86 and CD28, thereby preventing full T-cell activation. Since human CTLA4 can bind to rodent CD80 and CD86, this human fusion protein can be studied in rodent models [7], [8], [9], [10], [11], [12]. In particular, collagen type-II-induced arthritis (CIA) is an experimental rodent-based model of arthritis that has been used to investigate the pathogenesis of human RA and to identify potential therapeutic targets. Previous studies have demonstrated the efficacy of both murine CTLA4-Ig and human CTLA4-murine Ig constructs in inhibiting the onset and progression of disease in these rodent-based models [11], [12]. These versions of CTLA4-Ig are structurally different from abatacept. In addition, the efficacy of abatacept in treating the signs and symptoms of patients with RA has been demonstrated in a recent clinical trial [13].
In order to gain further insight into the mechanism of action of abatacept, this study examines the effects of abatacept on disease induction, joint inflammation, bone destruction and the production of inflammatory mediators in a rat model of CIA.
Section snippets
Cytotoxic T lymphocyte-associated antigen-4 immunoglobulin-4 and control immunoglobulin
Abatacept and control IgG (chimeric L6 monoclonal antibody) used in this study were provided by Bristol-Myers Squibb, Princeton, NJ.
Collagen-induced arthritis model
Female dark agouti (DA) rats were immunized subcutaneously at the base of the tail on day 0 with 300 μg of bovine type-II collagen in incomplete Freund's adjuvant. Immunized rats were segregated into three groups according to treatment modality. The first group received an injection of control human IgG 1 mg/kg intraperitoneally on days −1, 0, 2, 4, 6, 8 and 10. The
Abatacept prevents the development of inflammation in collagen-induced arthritis (CIA) rats
Arthritis developed rapidly in the DA rats after a single injection of type-II collagen in incomplete Freund's adjuvant as assessed by changes in paw volume. By day 16 following immunization, significant paw swelling was observed in the IgG-treated control animals compared with baseline levels, which continued to increase, reaching a plateau volume of approximately 3.0–3.5 ml on day 21 (Fig. 1). Compared with control IgG-treated arthritic animals, treatment with abatacept inhibited paw swelling
Discussion
The current study examined the effects of abatacept on disease induction and progression in CIA, a rat model of RA. The findings from this study suggest that prophylactic treatment with abatacept, through reduction in inflammatory mediators, prevents the onset of disease and bone destruction by downmodulating pro-inflammatory inhibitors that contribute to the induction of disease.
Rodent CIA is a well-established in vivo model that has been used in numerous studies to investigate the
Acknowledgements
The authors would like to thank Alison Bendele, DVM, Ph.D., DACVP of Bolder BioPath for her expert histological analyses and evaluation of the study tissues.
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2020, Life SciencesCitation Excerpt :Rats were used because though larger mammals, such as pig, are physiologically similar to humans, they are expensive, genetically heterogenous, require manipulation training especially, and are not well characterized at cellular and physiological level [19]. The sample size calculation was based on a study by Kliwinski et al. [13], which showed the need for six animals per group. This calculation was based on the reduction observed in this study of IL-1α expression from 50 ± 3 (mean ± standard error of the mean, n = 8) to 31 ± 4 (mean ± standard error of the mean, n = 8); the difference was assessed with Student's t-test, so that the sample represented 90% power and 95% confidence.
Effects of biological and targeted synthetic DMARDs on bone loss in rheumatoid arthritis
2019, Pharmacological ResearchCitation Excerpt :Furthermore, Bozec et al showed that CTLA4-CD80/86 signal can induce the production of the enzyme idoleamine 2,3-dioxygenase in osteoclast precursors, thus leading to a pro-apoptotic effect [108]. Of note, a study of Kliwinsky et al reported a reduced number of osteoclasts in mice treated with abatacept in concordance with the experimental models above [109]. A very interesting experiment on mice from Bedi et al. [110] proved that CTLA4 signaling can prevent bone loss and resorption induced by a continuous PTH stimulation in a non-arthritic setting.
Effects of targeted therapies on the bone in arthritides
2017, Autoimmunity ReviewsCitation Excerpt :Today, localized bone destruction may be detected by MRI, ultrasound or CT much earlier than by conventional radiography [1,16,76]. As a proof-of-concept, TNF-, IL-1-, IL-6R, IL-17 and IL-23 inhibitors, as well as CD80/86, CD20 and JAK inhibitors were able to block osteoclast activation, bone resorption and the development of joint erosions in animal models of arthritis [35,67,77–84]. Furthermore, in key clinical trials, the five available TNF-α inhibitors (infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol), as well as tocilizumab, secukinumab, ustekinumab, anakinra, abatacept, rituximab, tofacitinib and baricitinib were able to slow radiographic progression in both early and established RA or peripheral SpA [5,26,85–106].
Immunosuppressive effect of ASP2408, a novel CD86-selective variant of CTLA4-Ig, in rats and cynomolgus monkeys
2016, International ImmunopharmacologyAdvances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis
2013, Autoimmunity ReviewsCitation Excerpt :Recent studies overviewed here reveal that CTLA-4-Ig also impacts different T- and B-cell types involved in RA disease processes and pathology [31–36,47,48], and may be involved in directly downregulating cytokine production by macrophages [24,54]. Furthermore, CTLA-4-Ig has protective effects on bone via the inhibition of osteoclast differentiation, which may be independent of inflammation [61,62] (Fig. 1B). Through a literature search and from our own expertise and knowledge, recent publications relevant to the mechanism of action of CTLA-4-Ig in RA have been identified and discussed in this review.
- 1
Present address: Centocor, Malvern, PA 19355, USA.
- 2
Present address: Inflammation Pharmacology, Pfizer Global R&D, Ann Arbor, MI 48105, USA.