Previously Unrecognized Mechanisms That Turn the Immune System On and Off

September 1, 1995

A previously unrecognized biochemical mechanism by which the immune system reins in the tissue-destroying activities of T

A previously unrecognized biochemical mechanism by which the immunesystem reins in the tissue-destroying activities of T lymphocyteshas been identified by researchers at the Weizmann Institute inIsrael. Their studies centered on two key activities associatedwith T-cell invasion of infected tissues. One of them, the releaseof the enzyme heparanase that punches holes in the endothelialconnective tissue of blood vessels, enables the T cell to exitthe blood system and squeeze into an inflamed area

The other, the release by T cells of the signal protein TNF-alpha,sends out a rallying call to bring additional inflammatory cellsinto battle.

In a paper published in the Proceedings of the National Academyof Sciences (Vol 92, No 11), Prof. Irun Cohen and Dr. Ofer Liderof the Institute's Department of Cell Biology showed that thesetwo activities are interrelated. They found that small, specificallymodified sugar units released by the breakdown of sugar-containingpolymers in connective tissues are picked up by invading T cellsand other varieties of white blood cells. These sugar molecules,they observed, quench the ability of the cells to produce TNF-alpha.

Therefore when many blood cells are busy entering a particularinfected region, releasing many sugar molecules, the cells producereduced amounts TNF-alpha. This represents a newly discoveredcontrol mechanism that limits T-cell entry when sufficient numbersof these cells are already at work.

According to Cohen and Lider, this finding has great relevanceto autoimmmune diseases such as arthritis, multiple sclerosis,and thyroiditis.

In a previous study carried out with Drs. Dalia Gilat, Rami Hershkovitz,and Liora Cahalon of the Weizmann Institute and Dr. Israel Vlodvavskyof the Hadassah-Hebrew University Medical Center, Lider identifiedyet another possible regulatory mechanism of T-cell action --one that increases T-cell recruitment. This collaboration showedthat the connective tissue-breakdown enzyme heparanase can onlyoperate as an enzyme when acidity levels are high, conditionscharacteristic of inflammation and tumor growth, a finding publishedin the Journal of Experimental Medicine.

The researchers believe that normal levels of acidity, which serveto bind heparanase to the sugar-containing polymers in the extracellularsupporting matrix of organs without degrading these polymers,may serve to enable the T cells to migrate and interact with connectivetissue once they have left the blood stream and entered an inflamedtissue.

Heparanase is known to pave the way not only for T cells, butalso for mlignant metastases. "Therefore," says Lider,"we may some day be able to inhibit metastases by adjustingthe pH in the vicinity of a tumor, thereby preventing heparanasefrom clearing a path for cancerous cells."