BioWorld International Correspondent

LONDON - The discovery of a way of damping down the immune response to specific antigens could have important clinical implications for some transplant patients and for those with autoimmune diseases such as rheumatoid arthritis, diabetes and multiple sclerosis.

Lorantis Ltd., of Cambridge, UK, has been assigned the clinical and commercial rights to the new approach. The company says it has raised £25 million (US$43.3 million) from private equity venture funds to develop products that will use the strategy in the areas of transplantation, autoimmune disease and allergy.

Maggie Dallman, professor of immunology at Imperial College London, told BioWorld International, "The method exploits a naturally occurring mechanism that the body has to prevent immune responses to its own proteins."

The strategy depends on stimulating a cell-surface receptor called Notch, at the same time exposing the immune system to an antigen. That induces an immune response that involves expanding a subset of T cells that suppresses the response to that particular antigen. Dallman said, "Rather than the protective immunity that you might see when you vaccinate, our protocol acts like a reverse vaccination strategy."

An account of the team's discovery appears in the Journal of Clinical Investigation, December 2003 issue, in a paper titled "Notch ligation by Delta 1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism."

When Dallman and her colleagues embarked on their investigation, they already knew that cell-surface proteins called Notch played an important role in embryonic development by dictating which differentiation pathways cells should follow. They also were aware that the Notch proteins continued to be expressed in cells of adult animals.

Their theory was that Notch and the protein that interacts with it (the Notch ligand) also could control the fate of cells of the immune system in adults, by dictating which types of cells they should become.

"We wondered whether - if this pathway was active at the time of antigen exposure - it might be possible to trigger a completely different type of immune response," Dallman said.

The team had "little idea" what the outcome would be, she said. It turned out that the strategy stimulated the expansion of suppressor T cells, the cells that normally prevent people from making immune responses to their own proteins.

To test the role of the Notch pathway in organ rejection, the researchers transplanted a heart into the abdomen of a mouse. The heart was connected by two major vessels to the recipient's blood supply, so it had a beat but did not pump blood around the body.

Two weeks before the procedure, some of the mice were exposed to a pre-treatment regimen that involved giving them tissue from the animal that would later donate its heart, together with some DNA encoding the Notch ligand. When those mice and the control mice later received the transplanted hearts, the animals that had been pre-treated took up to four times longer to reject the donated organs than the controls.

Further studies suggested that all the mice eventually rejected the hearts because the T-suppressor cells induced by the experiments only prevented one method of rejection.

Dallman said: "Rejection can occur by two mechanisms - either directly, where immune cells recognize transplant tissue as foreign, or indirectly, through communication with other immune cells. The approach we used only targeted the direct method of rejection, but we believe that our approach will be equally effective against the indirect route when appropriately applied." The team plans to tackle that question soon.

Investigating other ways of stimulating the Notch ligand also is on their agenda. "We want to be able to give the Notch signal to a person without having to give them DNA," Dallman said.

Lorantis already is developing proteins and small molecules that will have that function.

The approach could be harnessed in cases in which relatives donate organs or parts of organs. In the U.S., Dallman said, already about 50 percent of certain types of transplants are from live donors.

"If you had a drug you could give a couple of weeks before the planned transplant to stimulate the Notch receptor together with some blood, for example, from the donor, then by the time of the operation you would hope to have the right immune response in place," she said. That could open up the possibility of using gentler immunosuppressive regimens after transplant surgery. Even with organs from cadavers, she added, it might be possible to compress the time between the drug therapy and the transplant surgery.