Therapeutic Efficacy of Cord Blood-Derived Mesenchymal Stromal Cells for the Prevention of Acute Graft-Versus-Host Disease in a Xenogenic Mouse Model

Abstract

Human mesenchymal stromal cells (MSCs) have been successfully utilized for the treatment of refractory graft-versus-host disease (GvHD). Despite the large number of in vitro and in vivo models developed for clarifying their immunomodulatory properties, the mechanism of action of MSCs remains elusive and their efficacy controversial. Here, we tested the ability of cord blood-derived MSCs to alleviate the symptoms of GvHD induced by the injection of human peripheral blood mononuclear cells into NOD/SCID/γc(-) mice. In this in vivo xeno-GvHD model, we demonstrate that a single MSC injection is able to inhibit GvHD in terms of clinical signs and related mortality. We also show that in this model MSCs act by both immunomodulating T-cells and fostering recovery after irradiation. The translational impact of these findings could provide a reliable preclinical model for studying the efficacy, dosage, and time of administration of human MSCs for the prevention of acute GvHD.

Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs

“…This was effectively demonstrated by the ability of a single low dose (0.5 Â 10 6 ) of rapamycintreated UC-MSCs to significantly inhibit the onset of xenogeneic GVHD. The same number of untreated cells had no apparent effect, and, even a dose of 2 Â 10 6 , similar to that used in other studies [37,38], showed only a trend toward greater survival. Whereas rapamycin alone has been used for prevention of solid-organ transplant rejection and aGVHD in mice transplant models [30,31], doses of 3 Â 50 mg were insufficient in our experiments, as was a single dose of 50 ng that we calculate to be the approximate amount of drug introduced by the pretreated MSC (data not shown).…”

Third-party umbilical cord blood–derived regulatory T cells prevent xenogenic graft-versus-host disease

“…Previously, Cao et al, showed that when ex vivo expanded Treg were co-transferred with peripheral blood lymphocytes into the spleens of NOD/SCID mice, GvHD was prevented and survival significantly enhanced 29 . This model has also been used to study the GvHD-ameliorating effects of mesenchymal stem cells 30 . Similar to our findings, Hippen et al 4 , have previously shown that ex vivo expanded CB derived Tregs, expanded using both CD3/28 beads or cell based techniques, are able to inhibit xenogenic GvHD in a NK-deficient C57BL/6 Rag - / - , γc - / - mouse model 4 .…”

Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+T-Cell Activation by Inducing IL-10-Producing Th1 Cells

“…These cells are clinically attractive, as they show very low immunogenicity, and they can induce immunosuppression in vitro and in vivo [15], and available data from clinical trials indicate that they are safe and have shown some efficacy in ameliorating GvHD and autoimmune disease outcome in patients [2,[4][5][6][26][27][28][29][30]. However, their mechanism of action is still poorly understood.…”

“…Human CB-MSCs were obtained from CB mononuclear cells, and immortalized as previously described [15]. This cell line, which retains both the phenotype and differentiation capacity typical of freshly isolated MSCs, can be safely used for in vivo injection due to their characteristic cell-contact-induced growth arrest.…”

“…We took advantage of an immortalized CB-MSC line that we generated [15], and that we have shown to be effective in inhibiting xenogeneic graft-versus-host disease (GvHD) induced by human peripheral blood mononuclear cells (PBMCs) in a mouse model [15]. This CB-MSC line is also a very useful tool in terms of limiting experimental variability while increasing reproducibility.…”