Elsevier

Journal of Autoimmunity

Volume 25, Issue 3, November 2005, Pages 165-171
Journal of Autoimmunity

Prophylactic administration of abatacept prevents disease and bone destruction in a rat model of collagen-induced arthritis

https://doi.org/10.1016/j.jaut.2005.09.020Get rights and content

Abstract

Abatacept is the first in a new class of agents that selectively modulates T-cell activation by attenuating CD28-mediated co-stimulation. This study examined the effects of abatacept on disease development in a rat model of collagen-induced arthritis (CIA). The rats were treated with either abatacept (1 mg/kg) or control IgG beginning at the time of induction of CIA. By day 16, significant paw swelling was observed in IgG-treated control animals that continued to increase, reaching a plateau on day 21. Prophylactic treatment with abatacept completely abrogated paw swelling throughout the study. Histopathology demonstrated a significant reduction in inflammation, cartilage destruction, bone resorption and pannus formation. Abatacept treatment resulted in 90% inhibition of circulating collagen-specific antibodies and decreased the serum expression of many cytokines and chemokines that were upregulated in diseased animals. Immunohistochemical analysis of the ankle joints demonstrated that interleukin-6 production was reduced in the tissues and the numbers of osteoclasts present in the joints were also decreased. Ankle microcomputer tomography (micro-CT) analyses dramatically demonstrated the protective effects of abatacept on bone destruction in these animals. Data presented here demonstrate that prophylactic administration of abatacept significantly inhibits the onset and progression of disease in a rat CIA model, with reductions in inflammation, inflammatory mediators, and bone and joint destruction.

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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1

Present address: Centocor, Malvern, PA 19355, USA.

2

Present address: Inflammation Pharmacology, Pfizer Global R&D, Ann Arbor, MI 48105, USA.

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