Anti-inflammatory effects of a new tumour necrosis factor-alpha (TNF-α) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats

K ÅKerlund

H Harris

K Tracey

H Wang

^{Department of Rheumatology, Centre of Molecular Medicine, Karolinska, Sweden}

^{Department of Rheumatology, Astrid Lindgren's Children's Hospital, Karolinska Hospital, Stockholm, Sweden}

^{Laboratory of Biomedical Science, Picower Institute for Medical Research, Manhasset, NY, USA}

^{Department of Infectious Diseases, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden}

Correspondence: Karin Åkerlund MD, Department of Rheumatology, Centre of Molecular Medicine, Karolinska Children's Hospital, S-171 76 Stockholm, Sweden.

Accepted 1998 Sep 10.

Abstract

A recently developed compound, a multivalent guanylhydrazone (CNI-1493) that inhibits TNF-α production by suppressing TNF-α translational efficiency, was administered in an experimental model of collagen type II-induced arthritis in DA rats. CNI-1493 was injected daily intraperitoneally either before the onset of arthritis or after the establishment of clinical disease. Prophylactic treatment with CNI-1493 significantly prevented or delayed the onset and suppressed the severity of arthritis in a dose-dependent manner. Therapeutic intervention with CNI-1493 in established joint disease also resulted in a significant reduction of clinical signs of arthritis in treated animals. No severe side-effects were noted when animals were treated with daily CNI-1493 doses up to 5 mg/kg. An immunohistochemical study was performed which demonstrated that CNI-1493 led to a reduced expression of TNF-α at the site of disease activity. Thus, CNI-1493 with documented inhibitory effects on TNF-α synthesis, has proven successful in ameliorating the course of arthritis in CIA. We believe that the use of a compound such as CNI-1493 with a defined mode of action provides a useful tool for dissecting and understanding important pathogenic mechanisms operating in the development of chronic arthritis.

Keywords: collagen-induced arthritis, immunotherapy, tetravalent guanylhydrazone, immunopharmacology, tumour necrosis factor-alpha

Abstract

Acknowledgments

The authors would like to thank R&D Systems for the kind gift of the goat anti-rat TNF-α antibody and Dr Peter van der Meide (BPRC, Rijswijk, The Netherlands) for the rabbit anti-rat TNF-α antibody. We would also like to thank Dr R. A. Harris for rewarding linguistic advice. This work was supported by grants from the Swedish Medical Research Council (grant nos 09082 and 10850), von Kantzow's Foundation, King Gustaf V:s Foundation, M Philipson's Foundation, NIH grants R01 DK49283 (K.J.T.), A Faculty Fellowship Award from the American College of Surgeons (K.J.T.), a grant from Cytokine Network, Inc., Institutional Funding from the Picower Institute, the Swedish Association against Rheumatism, Börje Dahlin's Foundation, Nanna Svartz' Foundation and af Ugglas' Foundation.

Acknowledgments

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