Scientists at Harvard and Stanford universities havediscovered a common pathway for the actions of two immunesuppressing drugs, a route that may lead to improvedimmunosuppressants with fewer toxic side effects.

As reported Friday in the journal Cell, the two teamscollaborated to determine that both cyclosporin, the drugisolated from fungi that has allowed heart and lungtransplants to succeed, and a new candidate for transplantmedicine, FK506, both act at a triad of calcium modulatingproteins.

The newly elucidated link between the two drugs -- a commonreceptor that receives the drugs when they are attached totheir binding proteins -- should allow the design of improvedimmunosuppressants, Stanford immunologist Irving Weissmantold BioWorld.

Selective immunosuppressants could also help in autoimmunedisorders such as rheumatoid arthritis, diabetes or lupus, inwhich the body attacks its own tissues.

An increase in calcium inside the cells is the first in a seriesof signals that activate T cells in the immune system andrecruit other immune cells, boosting the numbers of killer Tcells that attack foreign invaders. When the invader is atransplanted organ, however, this immune response is nolonger helpful.

Cyclosporin and FK506 halt the immune signals that lead totransplant rejection. But the drugs can damage the kidneys.

The calcium signal now might be targeted selectively inimmune tissues while avoiding the kidneys, Weissman said.

Harvard chemist Stuart Schreiber predicted that otherinhibitors soon will be found that will work by interferingdirectly with the calcium-generating signal.

Weissman's lab cloned a protein that allowed identification ofthe new cyclosporin target. Then Schreiber's team showed thata protein that it had found to bind FK506 matched thedescription of the cyclosporin target.

The Harvard group showed that the activity of this targetprotein, which is called calcineurin, is stopped when it bindseither of the two drugs.

Calcineurin could provide a rapid test-tube assay to screen formore selective drugs, Weissman said.

Stanford and Harvard have filed a joint patent applicationcovering the discoveries, and several companies haveexpressed interest in putting the technology to work in asearch for less toxic anti-rejection drugs, both investigatorssaid.

-- Roberta Friedman, Ph.D. Special to BioWorld

(c) 1997 American Health Consultants. All rights reserved.