Immunological Consequences of In Utero Exposure to Foreign Antigens

Abstract

Immunologic tolerance refers to a state of immune nonreactivity specific to particular antigens as an important issue in the field of transplantation and the management of autoimmune diseases. Tolerance conceptually originated from Owen’s observation of blood cell sharing in twin calves. Owen’s conceptual framework subsequently constituted the backbone of Medawar’s “actively acquired tolerance” as the major tenet of modern immunology. Based upon this knowledge, the delivery of genetically distinct hematopoietic stem cells into pre-immune fetuses represented a novel and unique approach to their engraftment without the requirement of myeloablation or immunosuppression. It might also make fetal recipients commit donor alloantigens to memory of their patterns as “self” so as to create a state of donor-specific tolerance. Over the years, the effort made experimentally or clinically toward in utero marrow transplantation could not reliably yield sufficient hematopoietic chimerism for curing candidate diseases as anticipated, nor did allogeneic graft tolerance universally develop as envisaged by Medawar following in utero exposure to various forms of alloantigens from exosomes, lymphocytes or marrow cells. Enduring graft tolerance was only conditional on a state of significant hematopoietic chimerism conferred by marrow inocula. Notably, fetal exposure to ovalbumin, oncoprotein and microbial antigens did not elicit immune tolerance, but instead triggered an event of sensitization to the antigens inoculated. These fetal immunogenic events might be clinically relevant to prenatal imprinting of atopy, immune surveillance against developmental tumorigenesis, and prenatal immunization against infectious diseases. Briefly, the immunological consequences of fetal exposure to foreign antigens could be tolerogenic or immunogenic, relying upon the type or nature of antigens introduced. Thus, the classical school of “actively acquired tolerance” might oversimplify the interactions between developing fetal immune system and antigens. Such interactions might rely upon fetal macrophages, which showed up earlier than lymphocytes and were competent to phagocytose foreign antigens so as to bridge toward antigen-specific adaptive immunity later on in life. Thus, innate fetal macrophages may be the potential basis for exploring how the immunological outcome of fetal exposure to foreign antigens is determined to improve the likelihood and reliability of manipulating fetal immune system toward tolerization or immunization to antigens.

Immunobiography and women's health: repercussions from conception to senility

“…Prenatal influences on immunobiography include numerous aspects, such as the health of future parents before conception, genetic predisposition, demographic and economic determinants, maternal health during pregnancy, and influences of the uterine environment and maternal biopsychic and cultural organisms during pregnancy 5 .…”

Fetal Kidney Transplantation for In Utero Fetuses

“…Fetuses develop immune tolerance to self-antigens and maternal antigens while growing in the maternal uterus 34). Attempts have been made to induce tolerance to foreign antigens by transplanting them during the fetal period, but the degree of tolerance acquisition varies, and consistent results have not been obtained 35,36,37). In the allogeneic transplantation in this study, the difference in the degree of tolerance may have influenced the difference in the degree of urine production.…”

Intraplacental injection of human iPSC-derived PDX1+ pancreatic progenitors prolongs Pdx1-deficient mice survival

“…To achieve in vivo organ generation in the future, studying the mechanisms by which human cells are rejected from animal embryos and developing strategies for efficiently transplanting human donor cells into animal embryos is essential. Previous studies have shown that the innate immune system plays an essential role in xenotransplantation (Azimzadeh et al, 2015; Chen, 2021; Ide et al, 2007) and that the contribution of human cells can be increased by suppressing their apoptosis (Zheng et al, 2021). However, as shown in the current study, phenomena caused by distant interspecies chimerism, such as developmental abnormalities caused by the injection of an excess number of human cells, are poorly understood.…”