Mesenchymal stem cells (MSCs) suppress alloantigen-induced T-cell functions in vitro and infusion of third-party MSCs seems to be a promising therapy for graft-versus-host disease (GVHD).Little is known about the specificity of immunosuppression by MSCs, in particular the effect on immunity to pathogens.
We have studied how MSCs affect T-cell responses specific to Epstein-Barr virus (EBV) and cytomegalovirus (CMV). We found that EBV-and CMV-induced proliferation and interferon-␥ (IFN-␥
IntroductionHuman mesenchymal stem cells (MSCs) can differentiate into a variety of tissues, including bone, cartilage, and muscle. 1 MSCs are found in low frequency in the bone marrow but can be isolated and expanded in vitro. One important feature of MSCs is their immunoregulatory functions. MSCs suppress alloantigen and mitogen-induced proliferation, 2-4 interferon-␥ (IFN-␥) production, 5 and cytolytic killing 6,7 in vitro in a manner not restricted by the major histocompatibility complex (MHC), 3 but the mechanisms of suppression by MSCs are still largely unclear. MSCs also seem to escape recognition of alloreactive cells. 3,[8][9][10] The immunomodulatory effects of MSCs in the allogeneic setting have provided a rationale for the clinical use in graft-versus-host disease (GVHD). Severe acute GVHD after allogeneic stem cell transplantation (SCT) is associated with high mortality, but infusion of third-party MSCs seems to be a promising therapy for GVHD refractory to conventional immunosuppressive treatments. 11,12 Very little is known about the specificity of immunosuppression by MSCs and, in particular, the effect on cell-mediated immunity to infectious pathogens. This is an important issue, because infections are a major cause of morbidity and mortality after allogeneic SCT, particularly in the setting of intensive immunosuppression required for the treatment of GVHD. Two major viral pathogens in this setting are cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Between 40% and 70% of stem cell transplant recipients who are CMV-seropositive or have a seropositive donor develop CMV reactivation. [13][14][15] EBV reactivation may result in posttransplantation lymphoproliferative disease (PTLD) and occurs in 11% to 26% of SCT patients in whom selective T-cell depletion has been used for prevention of GVHD. [16][17][18] Antiviral T-cell effector functions are essential for preventing viral reactivation and progression to virus-associated disease. Thus, if MSCs have regulatory effects on antiviral cell-mediated immunity, administration of MSCs to immunocompromised patients could exacerbate their susceptibility to infectious pathogens. Indeed, at least one patient treated with MSCs for GVHD developed EBV-associated PTLD, and there have been several cases of CMV reactivation after MSC infusion. 12 However, there is insufficient clinical experience to determine whether administration of MSCs affects the development of virus-associated disease. We have therefore systematically studied how MSCs affect antiviral T-cell effector func...