Redirecting reproductive immunology research toward pregnancy as a period of temporary immune tolerance

Referring to two recent publications, we here propose that clinical reproductive immunology has for decades stagnated because reproductive medicine, including assisted reproduction (AR), has failed to accept embryo implantation as an immune system-driven process, dependent on establishment of maternal tolerance toward the implanting fetal semi-allograft (and complete allograft in cases of oocyte donation). Pregnancy represents a biologically unique period of temporary (to the period of gestation restricted) tolerance, otherwise only known in association with parasitic infections. Rather than investigating the immune pathways necessary to induce this rather unique state of tolerance toward the rapidly growing parasitic antigen load of the fetus, the field, instead, concentrated on irrelevant secondary immune phenomena (i.e., “immunological noise”). It, therefore, does not surprise that interesting recent research, offering new potential insights into maternal tolerance during pregnancy, was mostly published outside of the field of reproductive medicine. This research offers evidence for existence of inducible maternal tolerance pathways with the ability of improving maternal fecundity and, potentially, reducing such late pregnancy complications as premature labor and preeclampsia/eclampsia due to premature abatement of maternal tolerance. Increasing evidence also suggests that tolerance-inducing immune pathways are similar in successful pregnancy, successful organ transplantation and, likely also in the tolerance of “self” (i.e., prevention of autoimmunity). Identifying and isolating these pathways, therefore, may greatly benefit all three of these clinical areas, and research in reproductive immunology should be accordingly redirected.