Stromal cells-are they really useful for GVHD?

Mesenchymal stromal cells (MSCs) have immunomodulatory effects and are increasingly being used for the treatment of acute and chronic GVHD. Although they seem immuno-privileged, they induce alloresponses, but the risk of immunization is poorly characterized. After infusion, they first reach the lungs, liver and spleen, and are then difficult to trace. Several mechanisms are involved in stromal cells suppressing alloreactivity, such as induction of regulatory T cells, but whether or not this will also affect leukemic relapse or increase infections is not known. Although several encouraging pilot studies have been published, there have been few prospective randomized trials. There may be a bias in the literature, as negative results are seldom published, and there have been few comparative studies with other immunosuppressive regimens. Most animal models have failed to show any effect on GVHD. Several questions remain to be answered for optimization of stromal cell therapy. Which source is optimal-BM, fat, cord or decidua? Can stromal cells be replaced by exosomes, which culture conditions are most appropriate and at what passage and how frequently should cells be administered? More research is required to move stromal cell therapy forward to become an established treatment for acute and chronic GVHD.

A prospective randomized toxicity study to compare reduced-intensity and myeloablative conditioning in patients with myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation.

BACKGROUND: To our knowledge, no randomized toxicity studies have been conducted to compare myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in allogeneic haematopoietic stem cell transplantation (HSCT). METHODS: Adult patients ≤60 years of age with myeloid leukaemia were randomly assigned (1 : 1) to treatment with RIC (n = 18) or MAC (n = 19) in this Phase II single-centre toxicity study. RESULTS: There was a maximum median mucositis grade of 1 in the RIC group compared with 4 in the MAC group (P < 0.001). Haemorrhagic cystitis occurred in eight of the patients in the MAC group and none in the RIC group (P < 0.01). Results of renal and hepatic tests did not differ significantly between the two groups. RIC-treated patients had faster platelet engraftment (P < 0.01) and required fewer erythrocyte and platelet transfusions (P < 0.001) and less total parenteral nutrition (TPN) than those treated with MAC (P < 0.01). Cytomegalovirus (CMV) infection was more common in the MAC group (14/19) than in the RIC group (6/18) (P = 0.02). Donor chimerism was similar in the two groups with regard to CD19 and CD33, but was delayed for CD3 in the RIC group. Five-year transplant-related mortality (TRM) was approximately 11% in both groups, and rates of relapse and survival were not significantly different. Patients in the MAC group with intermediate cytogenetic acute myeloid leukaemia had a 3-year survival of 73%, compared with 90% among those in the RIC group. CONCLUSION: Reduced-intensity conditioning had several advantages compared with MAC, including less mucositis, less haemorrhagic cystitis, faster platelet engraftment, the need for fewer transfusions and less TPN, and fewer CMV infections. Both regimens were tolerated and TRM was low.

Stromal cells from term fetal membrane are highly suppressive in allogeneic settings in vitro.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) have immunosuppressive properties and have been used to treat steroid-refractory acute graft-versus-host disease (GVHD) in stem cell transplant patients. Cells with similar capacities can also be found in term placental tissue. We have isolated stromal cells from term fetal membrane (FMSCs), umbilical cords (UCSCs) and placental villi (PVSCs) as well as from bone marrow and compared their immunoregulatory capacity in allogeneic settings. We found that FMSCs and UCSCs suppressed proliferation significantly in mixed lymphocyte reactions (MLRs), whereas PVSCs showed inconsistent suppressive effects. When added to MLR cultures, FMSCs suppressed the production of interferon (IFN)-γ and interleukin (IL)-17, whereas UCSCs and PVSCs promoted the production of IL-17 instead. Secretion of IL-10 was increased after addition of FMSCs and UCSCs. In this setting, BM-MSCs had no significant effect on secretion of IFN-γ, IL-17 or IL-10 in MLR cultures. When analysing the expression of adhesion markers, we noted that FMSCs expressed the highest levels of CD29 (ß1), CD49d (α4) and CD54 (ICAM-1) compared to the other types of stromal cells. Thus, our data indicate that stromal cells isolated from term fetal membrane have great immunosuppressive capacity in terms of proliferation and production of proinflammatory cytokines from alloreactive T cells, and also promote anti-inflammatory IL-10. They express high levels of integrins that may be of importance in homing to inflamed tissues. Fetal membrane may provide a valuable source of cells with immunosuppressive properties and could possibly be used for treatment of acute GVHD and other inflammatory disorders.