Fetal Membrane Cells for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease

Abstract

The placenta protects the fetus from the mother's immune system. We have previously found that fetal membrane cells (FMCs) isolated from term placenta prevent alloreactivity in vitro. FMCs share many features with bone marrow‐derived mesenchymal stromal cells (MSCs), which we previously introduced to treat severe acute graft‐versus‐host disease (GVHD). Here, we tested FMCs for treatment of steroid‐refractory acute GVHD. After two passages in culture, approximately 109 FMCs were obtained from one single placenta, although not all cells from passage 0 and passage 1 were used for expansion. The FMCs were positive for CD29, CD44, CD73, CD90, CD105, and CD49d but were negative for hematopoietic, endothelial, and epithelial markers. Microsatellite polymorphism analysis showed that FMCs were of maternal origin. All FMCs used showed normal karyotype. Nine patients who had undergone hematopoietic stem cell transplantation (HSCT) and who had developed steroid‐refractory grade III–IV acute GVHD were given 0.9–2.8 × 106 FMCs per kg at 15 infusions. Median age was 57 years. There was no toxicity from infusion of FMCs in eight patients. One patient had seizures after infusion. Two of eight evaluable patients had a complete response and four had a partial response, giving an overall response rate of 75%. Two patients showed no response at all. Three patients are alive from 6 to 21 months after HSCT. One patient is well and two have chronic GVHD. Thus, FMCs may be successfully used for immune modulation and tissue repair. STEM CELLS2013;31:592–601

Stromal cells–are they really useful for GVHD?

“…101 Stromal cells have a profound effect on coagulation, 18,20 which partly explains their effectiveness in stopping major hemorrhages. 90,102,103 BM must be accessed by aspiration, and this source of MSCs has been challenged by MSCs from adipose tissue, umbilical-cordderived MSCs and stromal cells from the placenta-such as DSCs. Placental stromal cells are accessible without any invasive procedure and with little ethical consideration.…”

“…However, this treatment needs to be optimized, combining it with the right immunosuppressive therapies. We need to learn more about the therapeutic potential of stromal cells in order to understand their mechanistic functions Adipose tissue 83,88 Umbilical cord 83,89 Placenta-derived decidua 83,90 Exosomes from stromal cells 76 Expansion media FCS 8,9,[82][83][84][85][86][87] Platelet lysate medium 83,85 AB serum 84 Regulatory T cells CD4 þ in the clinical setting. We have learnt that they are immunosuppressive and that they have regenerative properties, but so far these traits have only been confirmed in vitro.…”

“…90 We first compared three different sources of cells from the placenta: DSCs, stromal cells from umbilical cord and stromal cells from placental villi in vitro. 6 We found that DSCs exerted the most consistent inhibition of proliferation and inhibition of IFN-g and IL-17 production in mixed lymphocyte reactions compared with BM-MSCs and the other sources of stromal cells from placenta.…”

“…6,52 We therefore used DSCs for treatment of severe steroid-refractory acute GVHD of grades III-IV in nine patients. 90 Median age was 57 years and two patients had a complete response and four had a partial response.…”

A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation

“…6,7 Ambitious efforts to address this issue have included substitution of immunosuppressive pharmaceuticals, graft engineering, and cellular therapies. [8][9][10] In parallel, new immunosuppressive strategies have been evaluated in solid organ transplantation, making way for their introduction in HSCT. 11,12 A regimen that has shown promising results in prevention of GvHD is the combination of sirolimus and tacrolimus.…”