Prophylactic administration of abatacept (CTLA4-Ig; BMS-188667) prevents disease induction and bone destruction in a rat model of collagen-induced arthritis

Rheumatoid arthritis is an autoreactive disease in which activated T cells play an important role orchestrating the autoimmune responses giving rise to the inflammatory cascade responsible for joint inflammation and bone destruction. The CD28/B7 costimulatory pathway is critical for full T-cell activation, and modulating this pathway has been shown to inhibit T-cell activation leading to inhibition of these immune responses. Abatacept modulates T-cell activation by interfering with the engagement of CD80/86 with CD28. Abatacept has been shown to provide significant improvement in the signs and symptoms of rheumatoid arthritis in a phase II trial. Here, we examine the effect abatacept administration has on disease induction, anti-collagen antibody production and bone destruction in a rat model of collagen-induced arthritis.

Female DA rats were immunized subcutaneously on day 0 with 300 μg bovine type II collagen in incomplete Freund's adjuvant at the base of the tail. Immunized rats were administered either 1 mg/kg abatacept or a control human IgG IP on days -1, 0, 2, 4, 6, 8 and 10. Disease progression was monitored by measuring the paw volume in milliliters with a plethysmometer. Both hind paws were measured and the change in volume from baseline measurements (day 0) were recorded. At the conclusion of the study (day 27) serum samples were collected from each animal for measurement of collagen-specific antibodies by ELISA as well as serum cytokine measurements. Legs from the rats were removed and placed in formalin and prepared for histological analysis as well as analysis of bone morphology by micro-CT.

By day 16 of the study, significant paw swelling was observed in the IgG-treated control animals and continued to increase throughout the study until reaching a plateau (~3–3.5 ml) on day 21. Administration of abatacept abrogated paw swelling throughout the course of the study. The IgG-treated rats reached 100% incidence while no incidence was observed in the abatacept-treated group. Serum anti-collagen antibody levels correlated well with the paw swelling data where abatacept administration resulted in 90% inhibition of collagen-specific antibodies. We also found that abatacept decreased the expression of many of the circulating cytokines and chemokines that were upregulated in diseased animals. The micro-CT data revealed that abatacept treatment protects the bone from destruction as the knees and ankles of these rats appear to be normal.

Abatacept, a selective co-stimulation modulator, significantly inhibited the onset and progression of disease in a rat collagen-induced arthritis model. In these studies, paw swelling, collagen-specific antibodies and bone destruction were all inhibited by the treatment.

Affiliations

1. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA

   • C Kliwinski
   • , D Kukral
   • , J Postelnek
   • , B Krishnan
   • , L Killar
   • , S Nadler
   •  & R Townsend

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