[HLA-G: from feto-maternal tolerance to organ grafting]

Abstract

E.D. Carosella was the pioneer who demonstrated the protective role of the HLA-G molecule on trophoblasts, which form a shield protecting the fetus from the immune reaction of its mother and subsequent reject. This non-classical HLA class I molecule is first expressed on the fertilized ovocyte, thus enabling a uterine implantation and then on the surface of the placenta trophoblast where the classical class I and II antigens are absent. He brought the first demonstration ex vivo of the protector role of HLA-G molecule present on the surface of fetal cytotrophoblast cells versus the lysis carried out by maternal decidual uterine NK cells, in both semi-allogenic combinations (maternal uterine NK cells and their own fetal cytotropohoblast counterparts) and allogenic combinations (different maternal uterine NK cells and cytotrophoblasts from different fetuses). The blockage of this protein triggers off an important cytotoxicity towards the fetal cells. Furthermore, he showed that HLA-G molecules act as an inhibitor of the T-lymphocytes, NK cells and antigen presenting cells (APC). Through his discovery Carosella also shows for the first time the three major clinical consequences: I) HLA-G molecules are crucial, as an altered expression of these molecules would lead to abortion and failed pregnancies, i.e. recurrent spontaneous abortions and preeclamptic disease. The embryo expression of soluble HLA-G molecules is a mandatory prerequisite to implantation. II) In allogenic transplantation (heart, kidney and liver-kidney graft) the expression of HLA-G protein significantly reduces acute rejection and showed an absence of chronic rejections. III) Finally, this expression on the malignant cells has a negative functional impact in the anti-tumour response. So the expression of HLA-G molecule constitutes an escape mechanism from immunosurveillance, just as the fetal cells protect themselves from the aggression of maternal immune cells.