The age-old battle between the sexes is fought out at themolecular level between a man's "self" antigens and awoman's T cells specifically targeted against thosemasculine immunogens.
Thus, a skin graft from a male donor mouse to a femalerecipient suffers prompt rejection. (See BioWorld Today,Sept. 18, 1995, p. 1.)
This implacable, gender-oriented, immunologicalhostility becomes mysteriously placable only when a malesperm makes a female pregnant. The truce lasts throughnine months of gestation, so the woman's immune systemwon't reject her fetus, half of whose cells carry itsfather's histocompatibility antigens. Once that progenyexchanges the womb for the world, its mother's T cellsrevert to their normal pre-pregnancy, anti-male state.
One clue to this mystery is the fact that a woman withmultiple sclerosis or rheumatoid arthritis _ bothautoimmune diseases _ often experiences remissionduring a pregnancy. Meanwhile, her overall immunedefenses continue to function.
At the German Cancer Research Institute in Heidelberg,immunologist Bernd Arnold mused over this and similarphenomena, and took on the aim of learning "how theimmune system can be silenced in part."
Arnold told BioWorld Today: "The problem in organtransplantation, as well as in autoimmune disease, is thatimmunosuppressive drugs such as cyclosporine are used.These all-or-nothing agents suppress the immune systemin general, so that patients become more susceptible tobacterial and viral infections.
His goal, to find an antigen-specific means ofsuppression, led Arnold to pose the question: "Is there aphysiological situation in which nature manages tosilence only part of the immune system, and leave the restunaffected?" Therefore, he said, "we studied the maternalT-cell response of pregnant mothers against paternal[same-species] alloantigens."
Pregnancy Induces Anti-Paternal Tolerance
He knew that pregnant females are not entirelyimmunosuppressed; they react normally against viralinfection, for example.
"There is for sure father-mother immunological contact,"Arnold observed. "Fetal cells are found in the maternalblood, so there is communication."
He and his group constructed a colony of transgenic miceexpressing maternal T cells specifically directed at thepaternal alloantigen. "Because we have an antibodyagainst the binding site of this particular T cell receptor,"Arnold explained, "but not against other T cell receptors,we could identify and follow these T cells in themothers."
They were able to demonstrate, he said, what otherscientists have long assumed, "that these male-targetingmaternal T cells undergo a phenotypic change, theybecome tolerant, whereas other T cells are unaffected.
"That is," Arnold continued, "the mother's immunesystem is in part silenced. So this is exactly what we werelooking for."
Arnold heads a group of 10 investigators, focused ontolerance, in the German center's immunology andgenetics institute. He reported his finding in the currentissue of Science, dated Oct. 27, 1995, under the title: "Tcell awareness of paternal alloantigens duringpregnancy."
Into newly pregnant female mice, he and his co-authorsinjected a syngeneic (genetically identical) mouse tumor,transfected with a gene encoding the paternal alloantigen."Because the mother's tolerized T cells accept thistransgenic tumor, expressing paternal antigen," Arnoldexplained, "it is able to grow. Whereas non-pregnantfemales reject it."
However, when he and his team mated the same femaleswith other males, the antigens on the same tumorappeared irrelevant. "It was of course rejected by thepregnant mother, because her T cells saw it as foreign."
Maternal T-cell tolerance to paternal immunogens isinduced early in pregnancy, in response to the very samemale antigens those T cells attack before impregnation."Maintenance of tolerance," Arnold pointed out, "needsthe presence of the antigen. And in the situation westudied, once the mouse pups are born, there are nolonger any male antigens present, and therefore no needfor the female to remain tolerant."
Lessons For Anti-Immune Tolerance Measures
Arnold's finding, that pregnancy induces tolerance,answers one question, but raises a myriad of others:
"The next step for us," he observed, "will be to try to findout what is really the mechanism. Which fetal cells areresponsible for this tolerance induction? Are theyexpressed on the placenta? Found in the blood of themother? We do not know."
Nor do he and his team know "whether this tolerance isnecessary for the success of the pregnancy, or just a by-product." Either way, Arnold observed "it would be veryinteresting, because we do not want to study pregnancyper se. We want to study how is it possible _ or is itpossible at all _ that under physiological conditions partof the immune system can be silenced?"
In short, "How does nature do it in the case of pregnancy?If we can learn this, then we may be able to specificallysilence T lymphocytes in an adult individual with anorgan graft or an autoimmune disease."
Immunologist Polly Matzinger heads the section on T-cell tolerance at the National Institute of Allergy andInfectious Diseases in Bethesda, Md.. As such, she isfamiliar with Arnold's work in Heidelberg.
"This is not the first time his finding [on tolerance inpregnancy] has been done," she told BioWorld Today,"but it's new and sexy. It's a nice system."
Enlarging on this comment, Matzinger's medical stafffellow, reproductive immunologist Elizabeth Bonney,said:
"Old studies have shown that pregnancy or multiplepregnancies will give you specific tolerance towardpaternal antigens. Arnold's will be the first study that hasactually been able to track a single T cell receptor to aparticular antigen, and show this kind of mechanism,which they are saying is receptor down-modulation orsequestration."
Matzinger added: "Here we have the placenta maybedoing something to protect itself. Elucidating themechanism by which any tissue protects itself may helpus with organ transplants." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.