Immune system research holds hope for understanding recurrent miscarriages, helping transplant and cancer patients

December 26, 2000

A mother's immune system may attack a fetus from multiple fronts, by sending in killer T-cells, by producing antibodies that target fetal cells or by coating cells with a destructive, soluble blood factor called complement, according to researchers at the Medical College of Georgia.

The grim attack described by researchers may surprise immunologists who would expect the T-cell attack, but not complement, the lethal component of an immune response that more typically would attack invaders such as viruses and bacteria coated by antibodies made by B cells.

"We now know that the nature of the attack is somewhat different than we had assumed," said Dr. Andrew L. Mellor, immunologist and chief of the MCG Program in Molecular Immunology. "We assumed that the maternal T-cells would get activated by fetal antigens, expand in number, then start to kill fetal cells and we cannot exclude that at this point." But in research published in the January issue of Nature Immunology, they also found deposits of complement B a component of the innate immune system which neutralizes foreign objects such as invading bacteria or virus coated by antibodies. In a normal immune response, T-cells come in to attack and destroy viral-infected cells while antibodies and complement attack bacteria and viruses still floating around in the bloodstream. Antibodies coat viral cells, activating the complement deposition and eventually killing the virus.

"What has not been resolved by our research is the connection between activating the maternal immune response and, as an end point, depositing complement," Dr. Mellor said. "The broad assumption has been that there is not a connection between T-cells and complement." To further explore new evidence that there may be, the MCG researchers already are looking at a model that has a factor produced by T-cells which may activate the complement.

They say the increased understanding of the maternal immune system's response has implications for better understanding recurrent miscarriages as well as for development of drugs which can manipulate the localized response to help a transplant patient keep his new organ and to help a cancer patient "reject" his tumor.

The MCG research team, led by Dr. Mellor and Dr. David Munn, described in the August 1998 edition of Science a mechanism for localized suppression of the mother's immune system that enables the fetus to escape attack. They found that during pregnancy, cells in the placenta trigger an isolated suppression of the mother's immune system so it doesn't reject the genetically foreign fetus. The cells express the enzyme indoleamine 2,3-dioxygenase, or IDO. IDO disables the immune system by degrading tryptophan, an amino acid essential to the survival of T-cells. When they blocked expression of IDO, pregnant laboratory mice rejected the fetuses every time.

The researchers were further exploring what happens when you block the protective mechanism, when they found the unexpected immune system response.

When they blocked the IDO mechanism, they found that complement was involved in the lethal destruction of the fetus. To determine if antibodies would explain the presence of complement, they looked at a mouse model with no maternal B-cells, the cells which make antibodies. Still the complement appeared to destroy fetal cells. "What that tells us is that T-cells somehow cause complement to be activated and deposited, which is a departure from classic immunology," Dr. Mellor said. Researchers from Washington University in St. Louis, who are co-authors on the study, first showed laboratory evidence that complement could attack the fetus in the February issue of Science.

They reported that mice fetuses without complement inhibitory factor B needed to protect all cells from complement attack B died due to complement deposition.

"The complement deposition opens a completely different way of looking at how the immune system response causes tissue damage and destruction," Dr. Mellor said. "The implication is that maybe we should look for complement deposition whenever we suspect T-cells might be activated." As an example, it has been assumed that T-cells destroy transplanted organs, and it may be that complement has a role as well, he said.

Related work in tumor immunology, being done in collaboration with investigators at H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, indicates that tumors are using some of the same mechanisms the fetus uses to escape the immune system. Early studies have shown when the IDO mechanism is blocked in tumors, tumor growth isn't impacted much, but complement deposition occurs, indicating that the abnormal growths may be susceptible to complement-mediated destruction, Dr. Mellor said.
The Carlos and Marguerite Mason Trust and the National Institutes of Health provide funding for Drs. Mellor and Munn's research.

Medical College of Georgia at Augusta University

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