Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins.

Lider, Ofer; Baharav, Ehud; Mekori, Yoseph A.; Miller, T B; Naparstek, Yaakov; Vlodavsky, Israël; Cohen, Irun R.

doi:10.1172/jci113953

Cited by 190 publications

(132 citation statements)

References 20 publications

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“…To induce AA, 9-to 10-wk-old Lewis rats (seven per group) were inoculated intradermally at the base of the tail with 0.1 ml of CFA containing 10 mg/ml Mycobacterium tuberculosis (H37RA; Difco), as previously described (17). DSF (300 g/rat per application) or water as control was administered p.o.…”

Section: Aa Assaymentioning

confidence: 99%

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Marikovsky

Ziv

Nevo³

et al. 2003

The Journal of Immunology

185

112

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Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-α induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-α and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-α, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-α levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-α serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.

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Section: Aa Assaymentioning

confidence: 99%

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Marikovsky

Ziv

Nevo³

et al. 2003

The Journal of Immunology

185

112

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“…Indeed, previous studies have suggested a role for heparanase in various pathophysiological conditions, including tumor metastasis (Escobar Galvis et al, 2007;Vlodavsky and Friedmann, 2001), experimental autoimmune disease (Lider et al, 1989), amyloidosis (Li et al, 2005) and delayed type hypersensitivity (DTH) reactions . A role for heparanase in tumour metastasis is supported by the strong correlation between levels of heparanase expression and metastatic potential of B16 melanoma (Vlodavsky et al, 1999) and T lymphoma (Goldshmidt et al, 2002b) cells.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Waern

Jia

Pejler

et al. 2010

Molecular Immunology

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Heparanase is a heparan sulfate (HS) degrading endoglucuronidase that has been implicated in cell migration and inflammatory conditions. Here we used mice deficient of heparanase (Hpse -/-) to study the impact of heparanase on airway leukocytes. Normal numbers of macrophages and lymphocytes were present in bronchoalveolar lavage fluid of Hpse-/-mice, indicating that heparanase is not essential for proper homing of leukocytes to airways. While lymphocytes fromHpse -/-mice displayed normal morphology, Hpse -/-alveolar macrophages showed a striking, age-dependent appearance of granule-like structures in the cytoplasm.Transmission electron microscopy revealed that these structures corresponded to membrane-enclosed crystalline bodies that closely resembled the intracellular crystals known to be formed by the HS-binding protein Ym1, suggesting that heparanase deficiency is associated with intracellular Ym1 deposition. Indeed, applying immunocytochemistry, we found markedly higher levels of intracellular

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“…The closely related molecule heparan sulphate is, however, found on vascular endothelial cells, where it is considered to play a role in preventing non-speci®c adhesion of blood elements since it is now known that certain in¯ammatory cells, most notably lymphocytes, release heparan-degrading enzymes in order to aid their extravasation (reviewed by Vlodavsky et al, 1992) and that these enzymes are inhibited by heparin (Bar-Ner et al, 1987). Indeed, the inhibitory e ects of administered heparin on lymphocyte orchestrated processes such as graft vs host reactions (Gorski et al, 1991;Lider et al, 1989), delayed type hypersensitivity reactions (Sy et al, 1983) and allergic encephalomyelitis (Lider et al, 1990;Willenborg & Parish, 1988) are thought to involve heparanase inhibition. However, there is also evidence that heparin can a ect the entry of lymphocytes to lymph nodes and Peyer's patches (Bellavia et al, 1980), having potential consequences with respect to the recirculation of these cells.…”

Section: Introductionmentioning

confidence: 99%

The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical vein endothelial cells

Smailbegovic

Lever

Page

2001

British J Pharmacology

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1 The e ects of unfractionated heparin (UH) and a selectively O-desulphated derivative of heparin (ODSH), lacking anticoagulant activity, on the adhesion of human peripheral blood mononuclear cells (HPBMNC) to human stimulated umbilical vein endothelial cells (HUVECs), were investigated. 2 For comparison, the e ects of poly-L-glutamic acid (PGA), a large polyanionic molecule without sulphate groups and two di erent molecular weight sulphated dextrans (DS 5 k and DS 10 k) were studied. 3 UH (50 ± 1000 u ml 71 ) signi®cantly (P50.05) inhibited the adhesion of HPBMNC to HUVECs, stimulated with IL-1b (100 u ml 71 ), TNF-a (1000 u ml 71 ) or LPS (100 mg ml 71 ), when the drugs were added together with stimuli to HUVECs and coincubated for 6 h. Such e ects on adhesion occurred with limited in¯uence on expression of relevant endothelial adhesion molecules (ICAM-1 and VCAM-1). 4 UH (100 ± 1000 u ml 71 ), when added to prestimulated HUVECs, signi®cantly (P50.05) increased adhesion of mononuclear cells to endothelium at the higher concentrations tested, without any e ect on adhesion molecule expression. In contrast, the opposite e ect was observed when human polymorphonuclear leucocyte adhesion was examined, under the same experimental conditions, suggesting that the observed potentiation of HPBMNC adhesion is cell speci®c. 5 The e ects of UH on HPBMNC adhesion were shared by the non-anticoagulant ODSH (600 ± 6000 mg ml 71 ) but not by sulphated dextrans or PGA (300 ± 6000 mg ml 71 ). 6 Heparin a ects the adhesion of HPBMNC to stimulated endothelium, in both an inhibitory and potentiating manner, e ects which are unrelated to its anticoagulant activity and not solely dependent on molecular charge characteristics.

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Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins.

Abstract: The ability of activated T lymphocytes to penetrate the extracellular matrix and migrate to target tissues was found to be related to expression of a heparanase enzyme

Cited by 190 publications

References 20 publications

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical vein endothelial cells

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