Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell‐mediated immunity

Abstract

Previously we reported that activated T lymphocytes express a heparanase enzyme that degrades the heparan sulfate moiety of the proteoglycan of the extracellular matrix (ECM). Expression of the heparanase enzyme was found to be associated with the ability of activated T lymphocytes to penetrate blood vessel walls and accumulate in target organs. We recently found that relatively low doses of heparin administered to mice or rats inhibited T cell-mediated immune reactions. In the present study we investigated the effects in vitro and in vivo of the heparanase inhibitor, heparin, on the expression of T lymphocyte heparanase and on the ability of T lymphocytes to mediate a delayed-type hypersensitivity (DTH) reaction. We found that heparanase was induced by immunizing mice with antigen in vivo or by activating T lymphocytes with concanavalin A in vitro. Relatively low doses of heparin administered once daily in vivo (5 micrograms) or present in vitro (0.1 microgram/ml) inhibited the expression of heparanase induced by immunization or by concanavalin A incubation. Higher or lower doses of heparin did not have these effects. The same doses of heparin that inhibited expression of heparanase also inhibited the ability of the lymph node cells to migrate to a site of antigen and adoptively produce a DTH reaction. These findings suggest that modulation of cell-mediated immune reactions may be achieved by relatively low doses of heparin which inhibit expression of T lymphocyte heparanase.

Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response

“…The shaved abdominal skin of inbred BALB/c mice (The Jackson Laboratory, Bar Harbor, ME; groups of 10 females) was sensitized with 100 l of 2% (v/v) oxazalone dissolved in acetone/olive oil (4:1 (v/v)), applied topically (16). DTH sensitivity was elicited 5 days later by challenging the mice with 10 l of 0.5% oxazalone in acetone/olive oil, applied topically to each side of the ear.…”

Additive and synergistic effects of a low-molecular-weight, heparin-like molecule and low doses of cyclosporin in preventing arterial graft rejection in rats.

“…The effects of low-molecular-weight, heparin-like molecules on the rejection process were first described by Lider et al 15 in a mouse skin-allograft model. They reported that low doses of heparin-like molecules without anticoagulant effects altered T-lymphocyte functions in vitro 22 and in vivo. 15 Reports indicate that T lymphocytes have an endoglycosidase that specifically degrades the heparan sulfate side chains of the extracellular proteoglycans in vitro.…”

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

“…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.…”