Why is the fetal allograft not rejected?

¹ Department of Veterinary Microbiology and Pathology & Center for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-7040

^* To whom correspondence should be addressed. E-mail: cdavies{at}vetmed.wsu.edu.

	Abstract

In viviparous species, the conceptus must be protected from a potentially hostile maternal immune system. The major histocompatibility complex (MHC) is a genetic region that encodes MHC class I and class II proteins, which present peptide antigens to T lymphocytes and induce graft rejection. The MHC class II proteins are only expressed on professional antigen presenting cells. However, classical MHC class I proteins are expressed on all nucleated somatic cells. Protection of the conceptus from immune-mediated rejection involves down-regulation of classical MHC class I antigen expression on trophoblast cells, which form the external epithelial layer of the placenta, and maintenance of an immunologically favorable immunosuppressive environment in the uterus. Normally, bovine trophoblast cells do not express MHC class I antigens before d 120 of pregnancy. However, third-trimester trophoblast cells in the interplacentomal and arcade regions of the placenta express both classical MHC class I proteins, which could potentially induce fetal rejection, and non-classical MHC class I proteins. A human non-classical MHC class I antigen, human leukocyte antigen G (HLA-G), is an important immunoregulatory factor required for maintenance of pregnancy. In cattle, third-trimester MHC class I expression has no adverse effects and probably contributes to placental separation at parturition. However, somatic cell nuclear transfer (SCNT) conceptuses, the majority of which are aborted between d 30 and 90 of pregnancy, had trophoblast cell expression of MHC class I antigens before d 34 of pregnancy. In conjunction with increased trophoblast MHC class I expression, SCNT pregnancies exhibited a marked increase in the number of stromal lymphocytes in the uteri of surrogate dams. A retrospective study found that SCNT pregnancies established using MHC class I homozygous cell lines, where the immunological barrier is greatly reduced, had significantly improved fetal survival from d 28 to term (51% survival for MHC homozygous and 5% for MHC heterozygous SCNT fetuses). Consequently, it appears that the high rate of fetal mortality in SCNT pregnancies is due, at least in part, to inappropriate expression of trophoblast MHC class I antigens and immune-mediated placental rejection. This suggests that appropriate regulation of MHC class I genes is critical for immunological acceptance of an allogeneic conceptus.

Key Words: Abortion, Bovine, Immunology, Major Histocompatibility Complex, Reproduction