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Antileukoproteinase - Modulation of neutrophil function and therapeutic effects on anti-type II collagen antibody-induced arthritis

Sehnert, B; Cavcic, A; Bohm, B; Kalden, JR; Kutty Selva, Nandakumar LU ; Holmdahl, Rikard LU and Burkhardt, H (2004) In Arthritis and Rheumatism 50(7). p.2347-2359
Abstract
Objective. Antileukoproteinase (ALP) is a physiologic inhibitor of granulocytic serine proteases. The present study was undertaken to investigate its therapeutic benefit in an antibody-transfer model of erosive polyarthritis and to elucidate its potential to interfere with immune complex-dependent inflammatory pathways. Methods. Arthritis development was induced in male (BALB/c x B10.Q)F-1 mice by intravenous injection of two monoclonal antibodies specific for type II collagen and was quantified by clinical scoring and histopathology. Arthritis severity was assessed in a cohort of mice under systemic treatment with recombinant human ALP (daily doses of 0.1 mg for 5 days starting immediately after disease induction) in comparison with... (More)
Objective. Antileukoproteinase (ALP) is a physiologic inhibitor of granulocytic serine proteases. The present study was undertaken to investigate its therapeutic benefit in an antibody-transfer model of erosive polyarthritis and to elucidate its potential to interfere with immune complex-dependent inflammatory pathways. Methods. Arthritis development was induced in male (BALB/c x B10.Q)F-1 mice by intravenous injection of two monoclonal antibodies specific for type II collagen and was quantified by clinical scoring and histopathology. Arthritis severity was assessed in a cohort of mice under systemic treatment with recombinant human ALP (daily doses of 0.1 mg for 5 days starting immediately after disease induction) in comparison with untreated controls. Concomitantly, functional assays (phagocytosis, oxidative burst, fluorescence-activated cell sorting analysis of integrin expression) were performed on neutrophils upon in vitro stimulation by IgG-coated latex beads. Results. ALP treatment reduced arthritis incidence and severity and had a protective effect against cartilage and bone erosion. ALP inhibited the conversion of the leukocyte beta2 integrins into an active conformation upon Fc receptor stimulation of granulocytes. ALP bound to the actin-bundling protein L-plastin and down-modulated filamentous actin assembly in response to stimulation with IgG-coated latex beads in granulocytes. ALP exerted additional inhibitory effects on neutrophil functions associated with cytoskeletal reorganization, such as phagocytosis and oxidative burst. Conclusion. In addition to its antiprotease activity, ALP exerts a variety of blocking effects on neutrophil functions, probably due to modulation of cytoskeletal changes, that may contribute to this inhibitor's antiarthritis potential and qualify it as a multifunctional regulator of inflammatory responses. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis and Rheumatism
volume
50
issue
7
pages
2347 - 2359
publisher
John Wiley & Sons
external identifiers
  • wos:000222820300037
  • pmid:15248236
  • scopus:3142684490
ISSN
1529-0131
DOI
10.1002/art.20339
language
English
LU publication?
yes
id
667ef147-987e-4fff-b2ee-dd4a1930552f (old id 272586)
date added to LUP
2007-10-26 13:47:10
date last changed
2017-05-28 03:42:24
@article{667ef147-987e-4fff-b2ee-dd4a1930552f,
  abstract     = {Objective. Antileukoproteinase (ALP) is a physiologic inhibitor of granulocytic serine proteases. The present study was undertaken to investigate its therapeutic benefit in an antibody-transfer model of erosive polyarthritis and to elucidate its potential to interfere with immune complex-dependent inflammatory pathways. Methods. Arthritis development was induced in male (BALB/c x B10.Q)F-1 mice by intravenous injection of two monoclonal antibodies specific for type II collagen and was quantified by clinical scoring and histopathology. Arthritis severity was assessed in a cohort of mice under systemic treatment with recombinant human ALP (daily doses of 0.1 mg for 5 days starting immediately after disease induction) in comparison with untreated controls. Concomitantly, functional assays (phagocytosis, oxidative burst, fluorescence-activated cell sorting analysis of integrin expression) were performed on neutrophils upon in vitro stimulation by IgG-coated latex beads. Results. ALP treatment reduced arthritis incidence and severity and had a protective effect against cartilage and bone erosion. ALP inhibited the conversion of the leukocyte beta2 integrins into an active conformation upon Fc receptor stimulation of granulocytes. ALP bound to the actin-bundling protein L-plastin and down-modulated filamentous actin assembly in response to stimulation with IgG-coated latex beads in granulocytes. ALP exerted additional inhibitory effects on neutrophil functions associated with cytoskeletal reorganization, such as phagocytosis and oxidative burst. Conclusion. In addition to its antiprotease activity, ALP exerts a variety of blocking effects on neutrophil functions, probably due to modulation of cytoskeletal changes, that may contribute to this inhibitor's antiarthritis potential and qualify it as a multifunctional regulator of inflammatory responses.},
  author       = {Sehnert, B and Cavcic, A and Bohm, B and Kalden, JR and Kutty Selva, Nandakumar and Holmdahl, Rikard and Burkhardt, H},
  issn         = {1529-0131},
  language     = {eng},
  number       = {7},
  pages        = {2347--2359},
  publisher    = {John Wiley & Sons},
  series       = {Arthritis and Rheumatism},
  title        = {Antileukoproteinase - Modulation of neutrophil function and therapeutic effects on anti-type II collagen antibody-induced arthritis},
  url          = {http://dx.doi.org/10.1002/art.20339},
  volume       = {50},
  year         = {2004},
}