IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

Abstract

Graft versus host disease (GVHD), mediated by donor T cells, is a significant source of morbidity and mortality following allogeneic stem cell transplantation. Mesenchymal stem cells (MSC) can successfully treat ongoing graft versus host disease, presumably due to their ability to suppress donor T cell proliferation. Little is known about the potential of MSC to prevent GVHD. Here we show that bone marrow-isolated MSC can suppress the development of GVHD if given after donor T cell recognition of antigen. IFN-c was required to initiate MSC efficacy. Recipients of IFN-c -/-T cells did not respond to MSC treatment and succumbed to GVHD. MSC, pre-treated with IFN-c, became immediately active and could suppress GVHD more efficiently than a fivefold-greater number of MSC that were not activated. When given at the time of bone marrow transplantation, activated MSC could prevent GVHD mortality (100% survival, p=0.006). MSC activation was dependent on the magnitude of IFN-c exposure, with increased IFN-c exposure leading to increased MSC suppression of GVHD. Activated MSC present a new strategy for preventing GVHD using fewer MSC. Key words: Mesenchymal stem cell Á GVH disease Á IFN-c See accompanying commentary by Dazzi and Marelli-Berg IntroductionAllogeneic hematopoietic stem cell transplants have the potential to play a significant curative role in the treatment of malignant and non-malignant hematopoietic disorders, autoimmune diseases, and immunological deficiencies, and in the induction of transplantation tolerance [1][2][3][4][5][6][7][8][9][10]. Widespread application of this therapeutic modality is limited due to the morbidity and mortality of graft versus host disease (GVHD), which affects 50% of stem cell transplant recipients [11][12][13][14][15][16]. While grafts highly matched to the recipient, young donors, donor/recipient sex match, and posttransplant immunosuppression are strategies used to reduce the risk of GVHD [17], thus far, the greatest preventative measure has been intentional underutilization of stem cell transplantation. Theoretically, strategies aimed at preventing GVHD would target early initiating factors either during the inflammatory milieu created in the wake of tissue damage from conditioning regimens [18,19] or during T cell antigen recognition and proliferation [20,21]. Once the efferent effector phase occurs, donor T cell-mediated destruction of host tissues occurs and preventive strategies are replaced with treatment regimens [19].Mesenchymal stem cells (MSC) have been used in the efferent phase of GVHD to successfully treat ongoing, acute, steroidresistant GVHD [22,23]. In contrast, when given at the time of BM transplant, for the prevention of GVHD, the incidence of grade III/ IV GVHD was not significantly improved [24], suggesting the [26,27,29,30]. In addition, MSC do not suppress the modest T cell proliferative response to recall antigens [31]. These findings suggest MSC may exert their optimal effects during the events surrounding larger scale T cell activation and proliferat...

Mesenchymal Stromal Cell Infusions as Rescue Therapy for Corticosteroid-Refractory Adult Autoimmune Enteropathy

“…However, the benefit was transient, raising concerns about how long MSCs can maintain their immunologic activity in vivo and which mechanisms are involved. 15 In this regard, studies on intestinal graft vs host disease showed that MSCs are beneficial when infused at the time of full-blown disease. 8,15 This therapeutic window likely depends on the presence of an inflammatory milieu that attracts more MSCs and licenses them to exert their tolerogenic and im- munosuppressive functions.…”

“…15 In this regard, studies on intestinal graft vs host disease showed that MSCs are beneficial when infused at the time of full-blown disease. 8,15 This therapeutic window likely depends on the presence of an inflammatory milieu that attracts more MSCs and licenses them to exert their tolerogenic and im- munosuppressive functions. 16 The recruitment of other immune cells may contribute to the therapeutic effect of MSCs, thus suggesting that MSC persistence is not a crucial prerequisite for their efficacy.…”

The role of the microenvironment on the fate of adult stem cells

“…In a non-inflammatory environment, bone marrow derived murine MSCs constitutively express low levels of cyclooxygenase-2 (COX-2), prostaglandin-2 (PGE-2), TGF-β1 and HGF, but not IL-10, programmed death-1 (PD-1), PD-L1 or PD-L2. In a pro-inflammatory environment, interferon-γ (IFN-γ) and IDO expression induced PD-L1 expression, which upregulated and enhanced their immunosuppressive effects after transplantation [92]. We have examined the expression of many pro-inflammatory cytokines/chemokines in BMSCs subjected to hypoxia treatment and observed down-regulated genes, such as CCL4, CXCR3 CXCL10, CC3, CC5 and CC17.…”

Human adipose-derived mesenchymal stem cell could participate in angiogenesis in a mouse model of acute hindlimb ischemia

“…ADSCs also increase the rate of synthesis of regulatory T cell associated with the modulation of the immune system (Aggarwal and Pittenger, 2005). Thus, ADSCs are considered as a superior source of cell therapy applications for the treatment of autoimmune diseases and controlling the graft versus host disease (Aggarwal and Pittenger, 2005;Polchert et al, 2008;Yanez et al, 2006).…”