Ground-breaking researchers at the Medical College of Georgia have uncovered more key and surprising clues about how a mother's immune system rejects a fetus. Their work in mice has potential implications for aiding organ transplants, targeting tumors and even thwarting the virus that causes AIDS.
The study by the team of Andrew Mellor, David Munn and others at MCG, along with researchers from Washington University in St. Louis, was published in the January issue of the prominent journal Nature Immunology.
The MCG team garnered international attention in August 1998 with an article in the journal Science proving the long-held suspicion that the fetus was like a foreign tissue transplant in the body but that it had a mechanism for locally disabling the mother's immune system. An enzyme called indoleamine 2,3 dioxygenase, or IDO, disables T-cells in the immune system by degrading tryptophan, which is essential for T-cell survival. When MCG researchers blocked IDO, the fetus was rejected.
Last year, the Washington group showed that removing the protein Crry exposed the fetus to being targeted by complement, a protein in a different part of the immune system than the MCG team was studying, and that resulted in miscarriage.
"What happens when complement is deposited on the cells is it is a flag for cells to come in and clear these cells out of the way," Dr. Mellor said. "It's foreign material that needs to be gotten rid of."
The MCG team also began studying it and found that when they blocked IDO and allowed the T-cells to target the foreign genetic material in the fetus, complement was still being deposited on the cells and they were still being targeted for destruction even when Crry - the protective protein - was there, Dr. Mellor said. And the destructive pathway worked even when there were no antibodies present, Dr. Mellor said.
"And the reason why that is a surprise generally to the immunology field is that complement is normally associated with antibody binding to cells first," Dr. Mellor said.
There is apparently a previously unknown link between the T-cells of the lymphocyte immune system and complement of the innate immune system, Dr. Mellor said.
"It's enough to block the mechanism (IDO) which stops the maternal T-cells from activating, and once you allow that (activation), complement is activated, it deposits on maternal-fetal interface, and that's the cause of the abortion," Dr. Mellor said. "That's what really generates the interest, the fact that you've connected two immune events, the T-cell activation and the complement activation deposition, which previously weren't connected, not in that order."
And it has given the researchers another pathway by which miscarriage may occur.
"Knowing the common pathways in the pregnancy loss system, which we use as our experimental model, drives interest in looking for similar opportunities to influence responses in tissue transplantation, perhaps even in anti-tumor therapies," Dr. Mellor said. When a miscarriage occurs, the researchers cannot rule out that it is the activation of killer T-cells to attack the foreign genetic material, as they first suspected, Dr. Mellor said.
The idea of being able to deliver localized IDO protection to a transplanted organ is an intriguing one to the researchers, Dr. Mellor said. The team is working with different models in mice to test these theories. Newly hired transplant and vascular surgeon Oscar Grandas said they will start heart and kidney transplants in mice in the next few months where some of the organs will be engineered to over-express IDO.
"We are trying to figure out what's (more) important, if the organ being transplanted over-expresses the enzyme or if it is important for the recipient over-express the enzyme," Dr. Grandas said.
While the supply of donor organs has grown in recent years, so has demand, said Kathy Lilly, assistant executive director of LifeLink of Georgia, the organ procurement system in the state.
"While it's gotten better and there's more public education and there's more avenues to reach people, the supply doesn't meet the demand," Ms. Lilly said. There are nearly 80,000 people in the U.S. waiting for a donor organ, and more than 1,100 in Georgia.
"In essence what that means is we have to focus again on doing the maximum possible to protect every donor organ because they are so valuable," Dr. Mellor said.
The MCG team is also working with researchers at the H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida to begin targeting certain tumors. Like the fetus, tumors seem to present a paradox that the immune system should recognize them and attack them but doesn't, Dr. Mellor said. The tumors may be using a similar mechanism to escape destruction.
"And if they do, then it's obviously a possibility that we could have some therapeutic value if we're right about them using the mechanism for their own protection," Dr. Mellor said.
The humanimmunodeficiency virus or HIV may be employing a similar method to elude the immune system, Dr. Mellor said.
"Again, it begs the question therapeutically of can we help the immune system to eradicate those tissues infected with infectious agents so that we clear chronic infectious diseases," Dr. Mellor said. "That's something we're very enthusiastic about at the moment."
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