Mesenchymal Stromal Cells Stimulate the Proliferation and IL-22 Production of Group 3 Innate Lymphoid Cells.

Infusion of mesenchymal stromal cells (MSCs) is a promising and increasingly applied therapy for patients who suffer from a variety of inflammatory diseases, including graft-versus-host disease (GvHD), a common and life-threatening complication after allogeneic hematopoietic stem cell transplantation. The therapeutic effect of MSCs is mainly ascribed to their ability to suppress T cells and to support tissue repair. However, clinical response rates in patients with GvHD are limited to 50%, and the determinants for MSC responsiveness are unknown. We recently reported that high frequencies of activated group 3 innate lymphoid cells (ILC3s) before and after allogeneic hematopoietic stem cell transplantation were associated with a lower risk of GvHD. This may be related to IL-22 production by ILC3s, a cytokine important for intestinal epithelial cell homeostasis. In this study, we investigated whether ILC3s may contribute to the therapeutic effect of MSCs by studying the interaction between MSCs and ILC3s in vitro. ILC3s isolated from human tonsils were cocultured with human bone marrow-derived MSCs for 5 d in the presence of IL-2. Coculture with MSCs enhanced the proliferation and IL-22 production of ILC3s. Reciprocally, ILC3s promoted ICAM-1 and VCAM-1 expression on MSCs. For both directions, the activation was mainly mediated by cell-cell contact and by MSC-derived IL-7 and likely by aryl hydrocarbon receptor ligands. Thus, in addition to inhibiting the proliferation of alloreactive T cells, MSCs also promote the expansion and IL-22 production of ILC3s, which may contribute to healthy homeostasis and wound repair in the treatment of various inflammatory conditions in the intestine, including GvHD.

The Potential of Mesenchymal Stromal Cells as Treatment for Severe Steroid-Refractory Acute Graft-Versus-Host Disease: A Critical Review of the Literature.

BACKGROUND: Acute graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation which causes high morbidity and mortality among patients who do not respond to steroid treatment. Mesenchymal stromal cells (MSCs) have immune modulatory abilities and earned their place in the treatment of GvHD after a pediatric patient remarkably recovered from steroid-refractory acute GvHD with MSC salvage therapy. Large, prospective clinical trials evaluating the potency of MSCs have however not been published. METHODS: To evaluate the therapeutic potential of MSCs in the treatment of steroid-refractory acute GvHD, we conducted a systematic literature search. We included all studies that focused on MSC treatment of adult allogeneic hematopoietic stem cell transplantation recipients with grades III to IV steroid-refractory acute GvHD and were transparent about their methods and patient selection criteria. RESULTS: From a total of 255 articles, 9 articles met the quality criteria for this study. The proportion of patients achieving complete resolution of all symptoms (complete response, CR) varied between 8% and 83%. Four of the 9 studies reported CR rates above 50%. The GvHD grade at the time of treatment was identified as a predictor of clinical response. Interestingly, complete response but not partial response to MSCs was associated with overall survival. No serious side effects of MSC therapy were reported. CONCLUSIONS: MSC treatment does improve the outcome in steroid-refractory acute GvHD patients but well-designed, prospective randomized clinical trials are needed to confirm the potential of MSCs as salvage therapy for steroid-refractory GvHD and to identify those patients that will benefit most.