Mesenchymal Stromal Cells for the Treatment of Graft Versus Host Disease

Abstract

Graft versus host disease (GvHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation, which is initially treated with high dose corticosteroids. Approximately 50% of acute GvHD cases are resistant to steroid treatment, and two-year mortality rates in those steroid-resistant patients exceed 80%. Chronic GvHD necessitates prolonged corticosteroid use, which is typically associated with limited efficacy and troublesome adverse effects. No agent has yet been established as an optimal second line therapy for either acute or chronic GvHD, but mesenchymal stromal cells (MSCs) have shown substantial promise. MSCs promote an immunosuppressive and immunoregulatory environment via multifactorial mechanisms, including: secretion of proteins/peptides/hormones; transfer of mitochondria; and transfer of exosomes or microvesicles containing RNA and other molecules. A large number of clinical studies have investigated MSCs from various sources as a treatment for acute and/or chronic GvHD. MSCs are generally safe and well tolerated, and most clinical studies have generated encouraging efficacy results, but response rates have varied. Confounding factors include variability in MSC donor types, production methodology and dose regimens, as well as variations in study design. It is well-established that extensive culture expansion of primary donor-derived MSCs leads to marked changes in functionality, and that there is a high level of inter-donor variability in MSC properties. However, recent manufacturing innovations may be capable of overcoming these problems. Further adequately powered prospective studies are required to confirm efficacy and establish the place of MSC therapy in the treatment of this condition.

Keywords: allogeneic; bone marrow transplant (BMT); graft versus host disease (GvHD); mesenchymal stromal (stem) cell (MSC); stem cell.

Figure 1

Mechanisms of action of MSCs in GvHD. MSCs may exert many effects on target cells via diverse potentially-overlapping mechanisms. Target cells include (i) donor and host immune cells, including T cells, B cells, NK cells, monocytes and dendritic cells; and (ii) host cells susceptible to damage by GvHD, e.g. cells of the skin, gastrointestinal tract and liver. Potential mechanisms through which MSCs may act include (A, B): transfer of exosomes or microvesicles containing RNA and other molecules; (C) paracrine activity including secretion of proteins (including IDO), peptides and hormones; (D) transfer of organelles via tunneling nanotubes; (E, F) MSC apoptosis results in the release of apoptotic extracellular vesicles that act on target cells, as well as induction of IDO production in recipient phagocytes.