Thein vivoeffects of tumour necrosis factor blockade on the early cell mediated immune events and syndrome expression in rat adjuvant arthritis

Abstract

SUMMARY Anti‐TNF therapy is effective in rheumatoid arthritis (RA); however, its mechanisms of action are incompletely understood. T cell‐driven mechanisms are thought to play an important role in RA and the effects of TNF blockade on these mechanisms are unclear. Adjuvant arthritis (AA) is a T cell dependent model of inflammatory arthritis. The aims of this study were to investigate the effects of TNF blockade on in vivo T cell cytokine expression and to clarify the role of TNF in the inguinal lymph nodes (ILN) in early arthritis. AA was induced in male DA rats. Rats received either 3 mg/kg or 10 mg/kg PEG sTNF‐RI at days 0, 2 and 4 postinduction or 10 mg/kg anti‐TNF antibody on day of arthritis induction. Control rats received either saline or normal sheep serum. Paw volume was assessed every 3–4 days. Rats were sacrificed on days 0, 6, 13 and 21 postinduction. Ankles were removed for quantitative radiology and histology. Synovium and ILN were removed for cell culture and to determine mRNA expression of cytokines using semiquantitative RT‐PCR. TNF and IFN‐γ protein production was measured using a bioassay and an ELISA. TNF blockade did not suppress mRNA expression of T cell cytokines in the ILN of rats in the early phase of AA, suggesting ongoing T cell activity. TNF protein production by ILN cells in culture was reduced in PEG sTNF‐RI treated rats, although mRNA expression was increased in the ILN prior to culture. Early administration of PEG sTNF‐RI did not attenuate AA, in contrast to an anti‐TNF antibody, which suppressed disease. A shorter half‐life for the PEG sTNF‐RI compared with the anti‐TNF antibody or the development of anti‐PEG sTNF‐RI antibodies may account for these results.

Exogenous tumour necrosis factor α induces suppression of autoimmune arthritis

“…Similarly, the treatment of rats with sTNF-RI beginning on day 4 after disease onset induced suppression of AA [30]. By contrast, in another study, sTNF-RI treatment of DA rats on days 0, 2, and 4 post-Mtb injection had no significant effect on early phase of AA [31]. However, later in the course of AA, lower dose of sTNF-RI exacerbated AA, while higher dose failed to alter the disease severity, supporting a concentration-dependent biologic effect of this pro-inflammatory cytokine [31].…”

Regulation of autoimmune inflammation by pro-inflammatory cytokines

“…TNF-α injection of TNFR1-deficient mice in early initiation phase of CIA aggravated the disease, whereas TNF-α administration in late initiation phase suppressed arthritis, again pointing to the opposite stage-dependent effects of this cytokine [66]. A study employing in vivo neutralization of TNF-α in the AA model also revealed differential effects on arthritis of the dosage as well as the timing of administration of sTNFR [67]. Taken together, these studies highlight the significance of the effects of temporal variations in TNF-α production during the course of arthritis and the resulting effects of the in vivo blockade of the cytokine.…”

A2A Adenosine Receptors Are Differentially Modulated by Pharmacological Treatments in Rheumatoid Arthritis Patients and Their Stimulation Ameliorates Adjuvant-Induced Arthritis in Rats

“…The treatment with A 2A AR agonists decreased the expression of inflammatory cytokines and the degree of oxidative and nitrosative damage [25]. Adjuvant-induced arthritis is a commonly used model of inflammatory arthritis, with an incidence of around 90%, making it an ideal model in which to investigate arthritic changes and to evaluate compounds that might be of potential use as drugs for RA treatment [26], [27]. Recently, A 2A AR agonists have been approved for clinical trials based on their anti-inflammatory and wound-healing properties [15], [28], [29].…”