Cotransplantation of mesenchymal cells and a higher relapse rate: a role for HLA-G molecules?

This is a Letter to the Editor to comment the paper by Ning et al (1) reporting a correlation between the cotransplantation of mesenchimal stem cells (MSCs) in allogeneic haemapoietic stem cell transplantation and a higher recurrence rate of malignant haematologic diseases. The authors concluded their paper suggesting that “the use of MSCs must be handled with extreme caution before a large-scale trials is performed”. Recently, several studies have reported the ability of MSCs, when co-cultured with activate peripheral blood mononuclear cells (PBMC) or directly activated by exogenous Interleukin 10, to modulate membrane bound and soluble HLA-G antigens (2-4). HLA-G antigens are non classical HLA-class I molecules characterized by tolerogenic and anti-inflammatory functions. In particular, both membrane and soluble HLA-G molecules have demonstrated to inhibit Natural killer (NK) and CD8+ T cell mediated cytolysis, CD4+ T lymphocyte proliferation and dendritic cell maturation. Moreover the expression of HLA-G antigens has been associated to the induction of regulatory T cells (4). Overall it is currently accepted that HLA-G molecules, by direct and indirect mechanisms, can inhibit innate and adaptative immune response. The production of sHLA-G molecules by MSCs (2-4) has suggested, in addition to other mechanisms, a rationale for the immunomodulatory properties of MSCs in preventing graft versus host disease (GVHD). Several researches have demonstrated that HLA-G modulation represents a beneficial event in organ transplantations, autoimmune diseases and pregnancy where the down-regulation of the immune response is essential for a positive outcome. On the opposite, the presence of HLA-G antigens has been associated to clinical negative consequences in cancer and viral infections where the tolerogenic function of these molecules permits to the mutated / infected cells to avoid the innate and adaptative immune response. In particular the HLA-G expression by cancer tissues and the relationship between plasma sHLA-G levels and cancer development (5-8) confirm the role of HLA-G molecules in sustaining the immune escape of cancer cells. The association between MSCs cotransplantation and malignant haematologic diseases development reported by Ning et al. (1) could be related to the functional ability of HLA-G molecules on one side to counteract GVHD but on the other side to permit the relapse of the disease. This hypothesis underlines the necessity of further studies to analyze plasma sHLA-G concentrations in MSCs cotransplanted patients in a longitudinal follow-up. The detection of a significant correlation between sHLA-G concentrations, GVHD prevention and relapse rate could identify a possible cut off in sHLA-G plasma levels responsible for the occurrence of these two phenomena.