title: Identification of a novel HLA-G+ regulatory population in blood: expansion after allogeneic transplantation and de novo HLA-G expression at graft-versus-host disease sites.
abstract: BACKGROUND
  The human leukocyte antigen-G (HLA-G) has been considered to be an important tolerogeneic molecule playing an essential role in maternal-fetal tolerance, which constitutes the perfect example of successful physiological immunotolerance of semi-allografts. In this context, we investigated the putative role of this molecule in the allogeneic hematopoietic cell transplantation setting.
  
  
  METHODS
  The percentage of HLA-G(+) cells in peripheral blood of healthy donors and allo-transplanted patients was evaluated by flow cytometry. Their immunoregulatory and tolerogeneic properties were investigated in in vitro immunostimulatory and immunosuppression assays. Immunohistochemical analysis for HLA-G expression was performed in skin biopsies from allo-transplanted patients and correlated with the occurrence of graft-versus-host disease.
  
  
  RESULTS
  We identified a CD14(+)HLA-G(pos) population with an HLA-DR(low) phenotype and decreased in vitro immunostimulatory capacity circulating in peripheral blood of healthy individuals. Naturally occurring CD14(+)HLA-G(pos) cells suppressed T-cell responses and exerted an immunotolerogenic action on T cells by rendering them hyporesponsive and immunosuppressive in vitro. After allogeneic hematopoietic cell transplantation, HLA-G(pos) cells increase in blood. Interestingly, besides an increase in CD14(+)HLA-G(pos) cells, there was also a pronounced expansion of CD3(+)HLA-G(pos) cells. Of note, CD3(+)HLA-G(pos) and CD14(+)HLA-G(pos) cells from transplanted patients were suppressive in in vitro lymphoproliferation assays. Furthermore, we found an upregulation of HLA-G expression in skin specimens from transplanted patients that correlated with graft-versus-host disease. Inflammatory cells infiltrating the dermis of transplanted patients were also HLA-G(pos).
  
  
  CONCLUSIONS
  We report the presence of naturally occurring HLA-G(pos) monocytic cells with in vitro suppressive properties. HLA-G expressing regulatory blood cells were found in increased numbers after allogeneic transplantation. Epithelial cells in skin affected by graft-versus-host disease revealed elevated HLA-G expression.
authors.affiliation: Department of Internal Medicine, Hematology Division, BMT Unit, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Lazana
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zoudiari
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kokkinou
authors.forename: Maria
authors.initials: M
authors.lastname: Themeli
authors.forename: Maria
authors.initials: M
authors.lastname: Liga
authors.forename: Helen
authors.initials: H
authors.lastname: Papadaki
authors.forename: Dionysios
authors.initials: D
authors.lastname: Papachristou
authors.forename: Alexandros
authors.initials: A
authors.lastname: Spyridonidis
mesh_terms: D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D016022:Case-Control Studies; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000097:blood* / Q000209:etiology; D059951:HLA-G Antigens / Q000097:blood*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D011379:Prognosis; D014184:Transplantation, Homologous
chemical_list: D059951:HLA-G Antigens