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THU0103 Therapeutical targeting of antigen-induced arthritis with liposomal secretory leukocyte protease inhibitor (antileukoproteinase)
  1. C Schneider1,
  2. S Söder2,
  3. B Sehnert1,
  4. RE Voll1,
  5. JR Kalden1,
  6. H Burkhardt1
  1. 1Department of Internal Medicine III, Institute for Clinical Immunology, Erlangen, Germany
  2. 2Institute of Pathology, Cartilage Research Group, Erlangen, Germany

Abstract

Background Alternative therapeutic principles for rheumatoid arthritis (RA) are still in urgent need. Secretory leukocyte protease inhibitor (SLPI), or antileukoproteinase (ALP), is a physiological serine protease inhibitor.1 Its upregulation in macrophages leads to a reduced LPS response2 most likely related to an inhibition of NF-kB by interference with the proteolytic degradation of its cytosolic inhibitor IkBbeta.3 However, the therapeutic use of this principle in vivo is hampered by difficulties to target the molecule into a cytosolic compartment. Phosphatidylserine containing liposomes can selectively be taken up by macrophages via Scavenger receptors4 thus representing a therapeutic strategy for targeting ALP to the cytosol.

Objectives In this preliminary study we applied a liposomal preparation of ALP in the murine antigen-induced arthritis (AIA) model to enhance intracellular accumulation in inflammatory cells to explore whether ALP can reduce inflammation.

Methods Liposomes were prepared by evaporation of a mixture of phosphatidylserine, phosphatidylcholine and cholesterol in chloroform/methanol and addition of ALP solution or PBS. Antigen-induced arthritis was induced in C57BL/6 mice by intraarticular injection of mBSA after prior immunisation with mBSA. Liposomal ALP was administered intraperitoneally (5 mg/kg/day) between days 1–4 after disease induction and compared with injections of PBS containing control liposomes or non-liposomal ALP. Arthritis was assessed by measuring knee joint diameter and evaluation of histological alterations in knee joint sections.

Results A marked amelioration of arthritis in mice treated with liposomal ALP was observed, already within 24 h after the first administration, while non-liposomal ALP was only moderately effective and control liposomes did not exhibit any effect. After induction of an arthritis flare on day 28, administration of ALP liposomes following the onset of acute inflammation again led to a marked reduction of joint swelling. Histopathological analysis of knee joints obtained from mice sacrificed at peak flare revealed that signs of acute (cellular infiltrate) and chronic arthritis (synovial proliferation, irregular cartilage surface, cartilage erosions) were exclusively diminished in the group treated with liposomal ALP.

Conclusion Taken together, the data indicate that therapeutic application of liposomal ALP reduces inflammation and consequently cartilage erosion in AIA. Therefore this form of antiproteolytic treatment might be considered as a novel therapeutic option in chronic inflammatory joint disease.

References

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  2. Zhu J, Nathan C, Ding A. Biochim Biophy Acta. 1999;1451(2–3):219–23

  3. Lentsch AB, Jordan JA, Czermak BJ, Diehl KM, Younkin EM, Sarma V, Ward PA. Am J Pathol. 1999;154(1):239–47

  4. Rigotti A, Acton SL, Krieger M. J Biol Chem. 1995;270(27):16221–4

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