Locally Activated Complement Components (LACC) Play Key Role in the Pathogenesis of Arthritis

Abstract

This study was to determine if LACC play a key role in collagen‐induced arthritis. Inhibition of LACC was achieved by intra‐articular (i.a.) injection of an anti‐C5 mAb, BB5.1, into already inflamed limbs (AIL). BB5.1 prevents the generation of C5a and C5b‐9. We selected an i.a. dosing that has no detectable effect on systemic complement activity (SCA) when given i.p. The therapeutic effect was evaluated by measuring the thickness of AIL and the number of newly recruited inflamed limbs (NRIL) during a 12d observation. Our results showed that i.a. injection of BB5.1 to AIL achieved significant therapeutic effect and reduced thickness of AIL from 5.08 ± 0.18 mm in controls to 4.62 ± 0.19 mm in an i.a. BB5.1 cohort. The same dose of BB5.1 by i.p. injection had no detectable impact on SCA, and resulted in no effect on AIL. Remarkably, i.a. C5 inhibition was sufficient to completely block the disease progression with no NRIL during the 12d period while animals in other cohorts all had a significant number of NRIL, ranging from a 300x increase in a cohort with i.a. injection of control mAb to a 240x increase in a cohort with i.p. injection of the same doses of BB5.1. Our data indicated that LACC are potent pro‐inflammatory mediators and play a key role in amplifying the downstream inflammatory process. Targeting C5a and C5b locally blocked the inflammatory amplification loop and achieved significant therapeutic effects without blocking SCA.