Differential effects of polysulfated polysaccharide on experimental encephalomyelitis, proliferation of autoimmune T cells, and inhibition of heparanase activity.
The extravasation of activated T lymphocytes through blood vessel walls and their migration to inflammatory loci are associated with secretion of extracellular matrix (ECM)-degrading enzymes, such as heparanase, which degrades heparan sulfate (HS) moieties of the ECM. The HS-degrading activity of heparanase was found to be inhibited by HS and heparin. Since induction of experimental autoimmune encephalomyelitis (EAE) requires extravasation and migration of autoimmune T cells, degradation of ECM by heparanase is expected to be involved in induction of the disease. Herein, we examined whether laminarin sulfate, a polysulfated polysaccharide (PSS) isolated from the cell walls of seaweeds and subjected to chemical sulfation, could inhibit ECM degradation by mammalian heparanase, and could prevent EAE. PSS was a more potent inhibitor of heparanase-mediated degradation of ECM than heparin. In-vivo, PSS, injected once a week, inhibited the severity of actively-induced EAE in rats. However, inhibition of EAE was not due to an overall suppression of autoimmune T cells, since PSS enhanced the proliferation of myelin basic protein (MBP)-specific, encephalitogenic T cells. PSS-activated autoimmune T cells, but not MBP-activated cells, failed to induce EAE in recipient rats. Moreover, rats injected with PSS-activated T cells were resistant to induction of EAE by anti-MBP CD4+ T cells. Thus, PSS may have potential clinical applications in the treatment of autoimmune diseases.
Hershkoviz
R
R
Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Mor
F
F
Miao
H Q
HQ
Vlodavsky
I
I
Lider
O
O
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D005260:Female; D005966:Glucuronidase; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects*; D011134:Polysaccharides / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013045:Species Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D000099175:Heparanase
D005966:Glucuronidase; D006026:Glycoside Hydrolases; D011134:Polysaccharides; D000099175:Heparanase; C053460:laminarin sulfate