A team of immunologists from Repligen Corp., Dana-FarberCancer Institute and Harvard Medical School have discovered anew molecule that appears to play a critical role in regulatingthe human immune response.

The researchers, led by Dana-Farber's Lee Nadler andRepligen's Gary Gray, reported in Friday's issue of Science thatthe new molecule, termed B7-2, appears to deliver the co-stimulatory signal necessary to activate immune system T cellsto perform their various functions, including as killers or asantibody-producers.

"We believe we've identified the control molecule that acts asthe on-off switch for T cells," Gray told BioWorld.

Understanding how the immune system's T cells becomeactivated is one key to being able to design drugs to controlthat process. Over the past several years, researchers havegained a fairly precise picture of the underlying mechanisms.They know that the activation of T cells by foreign antigens is atwo-signal phenomenon and that a specific recognition signalbetween the antigen (which is held by an antigen-presenting Bcell) and the T cell is essential.

But they also know that a second signal between the antigen-presenting cell and the T cell is necessary to actually generatethe immune response. For the past few years, scientists hadassigned that role to a molecule called B7-1 (found on thesurface of antigen-presenting B cells). But now it appears thatB7-1, though necessary for the immune response, is notresponsible for the immediate activation of T cells.

In fact, the researchers from Repligen, Dana-Farber andHarvard researchers now believe that role is played by thenewly discovered B7-2 molecule. Only later does B7-1 comeinto play. Since it's not expressed until several days after T cellstimulation, the researchers are now beginning to believe thatits role is to amplify the immune response rather than initiateit.

"Since B7-2 is continuously expressed by B cells, it may providean earlier signal than B7-1, which is not expressed until sometime after an immune response has been activated," said Dana-Farber's Nadler. "B7-2 may be the immune system's initial'decision-maker,'" he concluded.

And if the data hold, then the B7-2 switch molecule becomes alikely target for designing highly specific therapeutics that caninhibit an undesirable response without suppressing the entireimmune system (as does the drug-of-choice, cyclosporin A).

"If you can allow antigen presentation to occur normally butthen block the expression of B7-2, you can tolerize the T cellsso they never respond to that particular antigen again," saidRepligen's Gray.

This would have applications in autoimmune diseases such asmultiple sclerosis, rheumatoid arthritis and diabetes, as well asin organ transplantation, Gray added. "If you could disrupt theB7-2 signal at the time of organ transplant, you could makethis (particular) organ invisible from the immune systemforever."

Repligen of Cambridge, Mass., has obtained exclusiveworldwide rights from Dana-Farber to patents (applicationspending) covering B7 co-stimulatory molecules. The company(NASDAQ:RGEN) has exclusive rights to B7-1 patent applicationsowned by Dana-Farber of Boston in therapeutic andprophylactic fields. Repligen and Dana-Farber have jointly filedpatent applications on B7-2 and related molecules.

Dana-Farber will receive royalties from Repligen on net sales ofany products. All tolled, there are "over a dozen patentapplications, which cover all aspects of this aream includingcomposition of matter, use and means of manufacture, "explained Sandford Smith, Repligen's president and chiefexecutive officer.

-- Jennifer Van Brunt Senior Editor

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