Piece of Immune System Puzzle Identified, Offers Hope for Autoimmune Disease

An enzyme that helps the fetus avoid rejection by the mother’s immune system also is produced — at least in the test tube — by adult cells that help regulate the immune system, according to researchers at the Medical College of Georgia (MCG). The findings offer hope for stimulating healthy immune responses as well as suppressing autoimmune activity.

“Dendritic cells have multiple ways that they use to activate or suppress the immune system and many people working in the field are looking to find all the ways they do both those things; this is another way that can be added to the list,” said Dr. David Munn, pediatric hematologist-oncologist and lead author on the paper published in the Sept. 13 issue of the journal Science.

Dendritic cells are antigen-presenting cells that help the immune system decide what to attack or leave alone; scientists are studying them for a variety of purposes including their roles in autoimmune disease and for their potential in vaccines that prompt the immune system to attack a cancer. Still unclear is exactly how the cells handle the apparently opposite tasks of suppressing and activating the immune system, Dr. Munn said.

MCG scientists first found that the fetus was using the enzyme — indoleamine 2,3-dioxygenase or IDO — as a way to locally disable the mother’s immune system and avoid rejection. People have IDO in many places, especially places such as the respiratory and gastrointestinal tracts that are constantly bombarded with ‘foreign’ substances such as food and bacteria.

Now Drs. Mellor and Munn, in collaboration with researchers at the Veterans Affairs Medical Center in Augusta, H. Lee Moffitt Cancer Center in Tampa and the University of Virginia in Charlottesville, have found in the test tube that when the enzyme is expressed by adult human dendritic cells, it suppresses the proliferation of T cells. These cells rally the immune system to action. “There are cells in every person’s blood that can be encouraged, at least in the test tube, to develop this ability to turn T cells off,” Dr. Munn said.

“We knew in the placenta of mice that IDO helped control the mother’s T cells. So we asked if we could find cells expressing IDO in the adult immune system, purify those enzyme-expressing cells, put them with a ‘stranger’s’ T cells in a test tube and — just as in the fetus and a mother being two separate people coming in contact with each other — ask whether the cells that express the IDO enzyme would be able to suppress someone else’s T cells,” Dr. Munn said. “And the answer was, ‘Yes, it can.’”

Since the original finding was reported in 1998, scientists also have explored IDO’s potential in helping transplanted organs avoid rejection. IDO, which suppresses the immune system by degrading tryptophan, an amino acid essential to T-cell function, might one day have a role as well in treatment of tumors and persistent viruses such as HIV.

The MCG researchers have an inhibitor drug that blocks the IDO enzyme, allowing T cells to activate more effectively. MCG has patented or applied for patents on both the use of any drugs that would inhibit IDO and so help the immune system be more active as well as those that would encourage its expression and so inhibit the immune system.

In the current Science paper, the researchers speculate that the IDO expressing dendritic cells may play a role in the “immunologic unresponsiveness … of many cancer patients toward tumor-associated antigens,” but note that the extent of that role in a living human, as opposed to their test tube studies, must still be determined.

“We are very excited about this collection of technology. It’s in a critical area of medicine for which there is a pressing need for improvement: transplantation, AIDS and cancer treatment,” said Dr. Mike Gabridge, MCG associate vice president for technology transfer and economic development.

“Now that we know that IDO may be involved in allowing cells to be tolerant, we can look at chemicals that would up-regulate or down-regulate IDO and develop those as an approach to dealing with tolerance or promoting the immune response,” Dr. Gabridge said.

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