![]() The most recognized current concepts are that MSCs inhibit proliferation by arresting T cells in the G0/G1 phases of the cell cycle and perhaps by inducing T-cell apoptosis. Most likely, not all immune-suppressive activity of MSCs is relevant to every clinical setting. 43,44 The exact mechanism(s) of action of MSC-induced T-cell suppression in vivo is poorly understood for GVHD or any given clinical indication. 18-21, 41,42 Interestingly, it has been shown that MSCs only display suppressive activity against T lymphocytes when first primed with interferon-γ (IFN-γ), suggesting that this is the “active form” of MSCs for T-cell suppression. 22,23 Because these suppressive effects have been observed in cocultures when MSCs are separated from peripheral blood mononucleocytes via a Transwell membrane, MSC-modulated lymphocyte suppression seems to be due to paracrine mechanisms, including secreted mediators (eg, transforming growth factor-β, hepatocyte growth factor, prostaglandin E2), as well as metabolic activity (eg, indoleamine 2,3-dioxygenase). Focusing on T cells, MSCs have demonstrated the ability to suppress the proliferation of CD4 + and CD8 + activated T cells and inhibit the differentiation of CD8 + cytotoxic T cells. These immunomodulatory properties can effectively regulate the adaptive and innate immune responses, although additional research is required to understand which mechanisms occur in vivo. The immunomodulatory properties of MSCs have been extensively investigated in vitro and in vivo ( Table 1), providing significant implications toward applying MSCs to HCT. Here, we review key historical data in the context of the most salient recent findings to present the current state of MSCs as adjunct cell therapy in hematopoietic cell transplantation. Despite many challenges and much doubt, commercial MSC products for pediatric steroid-refractory GVHD have been licensed in Japan, conditionally licensed in Canada and New Zealand, and have been recommended for approval by an FDA Advisory Committee in the United States. Beyond GVHD, MSCs may facilitate hematopoietic stem cell engraftment, which could gain greater importance with increasing use of haploidentical transplantation. Moreover, the recently proposed concept of tissue tolerance suggests a new possible mechanism of MSC therapy for GVHD. The pathogenesis of GVHD reveals multiple potential targets. The key application of MSC therapy in hematopoietic cell transplantation is to prevent or treat graft-versus-host disease (GVHD). Although bone marrow–derived MSCs are the most commonly studied, the tissue source of MSCs may be a critical determinant of immunomodulatory function. Most recently, host macrophage engulfment of apoptotic MSCs has emerged as an important contributor to the immune suppressive microenvironment. Although the mechanisms of therapeutic activity in vivo are yet to be fully elucidated, MSCs seem to suppress lymphocytes by paracrine mechanisms, including secreted mediators and metabolic modulators. These fundamental properties suggest important applications in hematopoietic cell transplantation. Mesenchymal stromal cells (MSCs) are widely recognized to possess potent immunomodulatory activity, as well as to stimulate repair and regeneration of diseased or damaged tissue. ![]()
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