Abstract
After more than a decade of preclinical and clinical development, therapeutic infusion of mesenchymal stromal cells is now a leading investigational strategy for the treatment of acute graft-versus-host disease (GVHD). While their clinical use continues to expand, it is still unknown which of their immunomodulatory properties contributes most to their therapeutic activity. Herein we describe the proposed mechanisms, focusing on the inhibitory activity of mesenchymal stromal cells (MSCs) at immunologic checkpoints. A deeper understanding of the mechanism of action will allow us to design more effective treatment strategies.
Highlights
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that were first identified as a rare, non-hematopoietic cell in bone marrow that expands rapidly in vitro under standard culture conditions [1]
Inflammatory cytokines such as IFN-γ, tumor necrosis factor-α (TNF-α), and IL-1 are markedly increased in patients affected by acute graft-versus-host disease (GVHD), which potentially explains why clinical efficacy has been more conclusively demonstrated when there are mores severe manifestations of acute GVHD [55,56]
mesenchymal stromal cells (MSCs) induce the expression of CD39 and CD73 on certain T cell populations, resulting in increased adenosine concentrations in T cell cocultures [72]. These observations suggest that immune cells and stromal cells cooperate to restore adenosine triphosphate (ATP) balance following infection and injury, and further suggest that MSCs require the presence of specific immune cells to achieve maximum immunosuppressive effects [73]
Summary
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that were first identified as a rare, non-hematopoietic cell in bone marrow that expands rapidly in vitro under standard culture conditions [1]. Patients receive high-dose chemotherapy and are transplanted with hematopoietic and immune cells from a human leukocyte antigen (HLA)-matched donor, thereby replacing the diseased hematopoeitic system with that of a healthy donor It is the principal treatment for high-risk acute leukemia and the effectiveness in curing leukemias depends on the intensity of the conditioning regimen and the establishment of a graft-versus-leukemia immune response. Most evidence suggests that MSCs fail to meet their full immunosuppressive potential unless licensed by pro-inflammatory signals, which agrees with their established role in restoring homeostasis following infection and injury Inflammatory cytokines such as IFN-γ, TNF-α, and IL-1 are markedly increased in patients affected by acute GVHD, which potentially explains why clinical efficacy has been more conclusively demonstrated when there are mores severe manifestations of acute GVHD [55,56]
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