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- Open Access
Antileukoproteinase: modulation of neutrophil function and therapeutic effects in anticollagen II antibody-induced arthritis
© The Author(s) 2003
- Published: 12 September 2003
- Neutrophil Function
- Secretory Leukocyte Protease Inhibitor
- Arthritis Severity
- Arthritis Induction
- Intact Cartilage
Secretory leukocyte protease inhibitor, or antileukoproteinase (ALP), is a physiological inhibitor of granulocytic serine proteases.
The aim of the present study was to investigate the therapeutic effects of ALP in an arthritis model induced by the transfer of monoclonal antibodies (mAbs) to collagen type II (CII). Upon binding to the intact cartilage matrix, the intraperitoneally injected CII-specific mAbs provoke a massive infiltration of neutrophils into the joints and induce the development of an acute polyarthritis, leading to cartilage and bone destruction.
For arthritis induction, the combination of two mAbs to CII (CIIC1 and J1) were injected intraperitoneally into QB mice. After 3–4 days, untreated mice developed a polyarthritic disease. Arthritis severity was quantified by clinical scoring. The therapeutic effects of ALP upon systemic therapy with recombinant ALP (daily doses of 0.1 mg for 1 week, starting immediately after disease induction) were analyzed in a cohort of 12 mice in comparison with in untreated controls (n = 12).
First, ALP treatment resulted in a 50% reduction of arthritis incidence. Also, a marked amelioration of arthritis severity resulting in the reduction of clinical scores below 50% of untreated controls was observed in ALP-treated mice (P < 0.05). Finally, histopathological analysis of the joints revealed a protective effect of ALP treatment on cartilage and bone.
A concomitant functional analysis was performed in an in vitro system of Fc-receptor-stimulated neutrophils to elucidate immune-complex-dependent pathways that might be modulated by ALP treatment. In this model of neutrophil stimulation by IgG-coated Latex beads, a marked inhibitory effect of ALP on the induction of the conformational change of the leukocyte integrin LFA-1 into its active form could be demonstrated. Beyond this modulatory effect of ALP, affecting neutrophil adhesion to cytokine-activated endothelium, additional inhibitory effects could be demonstrated on the phagocytosis of immune complexes and the oxidative burst.
Taken together, the data indicate the therapeutic potential of ALP in the model of CII mAb-induced arthritis. Besides its antiprotease activity ALP seems to exert a variety of additional blocking effects on neutrophil functions such as adhesion, phagocytosis and respiratory burst, suggesting that it might be an important multifunctional regulator of inflammatory responses.