Transplant: why pregnancy can increase the risk of rejection

Although it is possible to carry out a pregnancy when one has benefited from an organ transplant, there is a risk of rejection of the graft for which one must be prepared. But how to explain it?

Researchers from the University of Chicago (USA) have looked into the matter. In a study published in the Journal of Clinical Investigations, they explain that during pregnancy, T-lymphocytes become tolerant to the fetus so that the latter can develop. At the same time, the part of the immune system that produces antibodies (called the humoral response) is sensitized, creating memory B-lymphocytes that can then contribute to the rejection of a transplanted organ. These results thus help to understand why the immune system can tolerate a fetus during pregnancy, but is more likely to be sensitized to an organ transplant and reject it afterwards.

When pregnancy upsets the immune system

The immune system is designed to respond and protect itself against foreign invaders. It does this by recognizing foreign cells, called antigens, and mounting an appropriate immune response: the production of T-cells that target and attack foreign cells, as well as those memory B-cells that produce antibodies to mark foreign cells for destruction by other blood cells.

During pregnancy, this system requires adaptation to prevent rejection of the fetus, which shares half of its genes with the mother and therefore presents foreign antigens to the mother’s immune system. This has the effect of increasing the risk of rejection of a transplanted organ (or allograft) after childbirth, particularly if the transplanted organ, such as a kidney, comes from the child’s father.

“It was paradoxical in the field of transplantation, where we see pregnancy as a sensitizing event, explains Anita Chong, professor of surgery at UChicago and co-lead author of the work. I wanted to know why pregnancy leads to sensitization to an allograft (transplanted organ) from the male partner, but increased tolerance to a fetus expressing the same antigens.”

Avoid allograft rejection

To find out, the researchers examined the immune response of female mice after receiving a transplanted heart from one of their offspring. By tracking both the T-cell response and the humoral response, they were able to track both arms of the immune response and study their effects on transplant rejection. They saw that the T-cells did not react to the allograft, but the memory B-cells did, producing antibodies against the foreign antigens of the transplanted heart.

How can this peculiarity be explained? According to the researcher and her team, both arms of the immune system would be sensitized to the transplanted organ paired with the offspring. “But there is something about the fetus promoting T-cell tolerance that is also preserved for the allograft. On the other hand, the antibodies that are produced for the fetus do not harm the fetus, but cause allograft rejectionProfessor Chong continues.

“Pregnancy cannot evolve to completely eliminate the humoral response, because it is essential for a mother to be able to produce antibodies against infectious pathogens during pregnancy and lactation; it is the only immunity a mother can transmit to her child. Thus, the immune system is ready to produce antibodies against anything foreign during this period, including those expressed by the fetus, develops the researcher. As a result, the placenta has developed means of manipulating these antibodies to prevent fetal rejection in subsequent pregnancies.”

Multiple therapeutic avenues

The challenge now is to develop therapies that would prevent the rejection of transplants in women after pregnancy. “This would level the playing field for women with children. We could eliminate antibodies and B-cells before transplantation and eliminate the problem, while T-cell responses to antigens shared by the fetus and transplantation would already be spontaneously partially suppressed”explains co-author Maria-Luisa Alegrez, professor of medicine at UChicago.

The other challenge that the team wishes to take up is “to exploit this capacity of pregnancy to tolerate T-cells so that they are better accepted not only by people who have been pregnant, but by everyone”. “Outside of pregnancy, people can be sensitized before transplantation in different ways, by diseases or environmental antigens, and it can be difficult to protect cross-reactive memory T-cell transplantation. We are now looking to know how pregnancy can tolerate these memory T-cells that are otherwise difficult to immunosuppress with current drugs.”