Soluble human leucocyte antigen-G molecules in peripheral blood haematopoietic stem cell transplantation: a specific role to prevent acute graft-versus-host disease and a link with regulatory T cells

Abstract

Haematopoietic stem cell transplantation is often complicated by the life-threatening graft-versus-host disease (GVHD) which consists of an allogeneic reaction of the graft cells against the host organs. The aim of this study was to investigate the putative involvement of soluble human leucocyte antigen (sHLA) class I molecules, and particularly sHLA-G molecules, in the occurrence and/or prevention of acute GVHD (aGVHD) in allogeneic peripheral blood stem cell (PSC) transplantation. Whole sHLA class I molecules seem to be involved in aGVHD pathogenesis because detection of a high concentration of these molecules in the first month post allograft is correlated with aGVHD occurrence. Conversely, a high level of sHLA-G molecules before and after allograft could indicate good prognosis in PSC allograft transplantation. sHLA-G molecules seem to be involved in aGVHD prevention, not only because they are enriched in plasma of patients without aGVHD, but also because: (i) a positive correlation has been found between sHLA-G level and CD4+ CD25+ CD152+ natural regulatory T cell (T(reg)) frequency in the blood of transplanted patients; and (ii) the presence of CD4+ CD25+ CD152+ natural T(reg) is correlated with increased sHLA-G expression in in vitro mixed leucocyte reaction cultures. Altogether, these results support the immunomodulatory function of sHLA-G molecules that might create a regulatory network together with the natural T(reg) to foster the induction of a tolerogenic environment and improve PSC transplantation favourable outcome.

The tolerogenic interplay(s) among HLA-G, myeloid APCs, and regulatory cells

“…48,49 They are also in agreement with those showing that high HLA-G5 plasma levels in the peripheral blood of stem cell-transplanted patients are associated with the expansion in peripheral blood of CD4 ϩ CD25 ϩ CD152 ϩ T cells with suppressive activity. 50 Soluble HLA-G up-regulated the expression of ILT2, ILT3, and ILT4 by lymphocytes and myeloid cell lines. 51 It is BLOOD, 15 DECEMBER 2011 ⅐ VOLUME 118, NUMBER 25 For personal use only.…”

The role of HLA–G 14-bp polymorphism in allo-HSCT after short-term course MTX for GvHD prophylaxis

“…The insertion of 14 bp is associated with a decreased mRNA stability and a consequent lower HLA-G protein expression. 4,13,14 Moreover, this polymorphism has a pharmacogenetic role in MTX treatment. Recent data have demonstrated that MTX induces higher HLA-G production in subjects homozygous for the 14 bp del allele influencing the response to the therapy.…”

“…2 HLA-G antigens function as immunomodulatory molecules inhibiting natural killer cell activity, CD4 þ T lymphocyte and DC maturation, inducing apoptosis in activated CD8 þ CTLs and the development of regulatory T cells. 3,4 In physiological conditions, HLA-G molecules are expressed by peripheral blood CD14 þ monocytes and thymic epithelial cells. HLA-G antigens have been detected in pathological conditions such as in autoimmune and inflammatory diseases, viral infections, 5,6 tumours 7,8 and in transplantation.…”

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

“…Indeed, there are data suggesting that an alloreaction itself might up-regulate the HLA-G expression. 36 In the only study analyzing the role of HLA-G in the allo-HCT setting, Le Maux et al 15 found increased soluble HLA-G plasma levels in patients without acute GvHD as compared to those patients with, and suggested a preventative role of this molecule in the occurrence of acute GvHD. In our study, we did not find any correlation between the frequency of the HLA-G pos cells and active GvHD, history of acute or chronic GvHD, severity of chronic GvHD or treatment with immunosuppressive drugs.…”

“…After allogeneic bone marrow transplantation, soluble HLA-G plasma levels have been suggested to correlate with the occurrence of acute graft-versus-host disease (GvHD), suggesting an involvement of HLA-G in GvHD prevention. 15 Unlike the highly polymorphic classic HLA class I molecules, HLA-G is expressed as only seven protein isoforms (HLA-G1 to -G4 membrane-bound and soluble HLA-G5 to -G7) that are generated by alternative splicing. 3 In vitro functional studies with membrane-bound HLA-G 16 or soluble HLA-G5 17 expressing cell lines have recognized the HLA-G molecule as an important mediator of immune tolerance, as it may: i) inhibit natural killer and T-cell cytotoxicity; ii) induce apoptosis in activated CD8 + T cells; iii) suppress alloreactive CD4 + T-cell proliferation; iv) generate suppressor T cells; and v) impair antigen-presenting cell function.…”