Mesenchymal stromal cells fail to alleviate experimental graft-versus-host disease in rats transplanted with major histocompatibility complex-mismatched bone marrow

Abstract

Mesenchymal stromal cells (MSC) can be used to treat graft-versus-host disease (GVHD) caused by allogeneic stem cell transplantation (allo-SCT). The effectiveness of this therapy has been variable in clinical trials and in experimental animal models. In this study, we investigated the ability of bone marrow (BM)-derived MSC to alleviate GVHD in an experimental rat model of allo-SCT using two different combinations of major histocompatibility complex (MHC) mismatch with survival as the primary endpoint. Recipient rats received total body irradiation and a transplant of T cell-depleted donor BM cells with either a full [PVG.7B → BN] or a partial MHC mismatch [PVG.1U → PVG.R23] restricted to the class II and non-classical class I sub-regions (RT1-B/D-CE/N/M). GVHD was invoked by infusion of graded doses of donor leukocytes 2 weeks after allo-SCT. Weekly doses of MSC were injected starting on the day of donor leukocyte infusion. No significant overall improvement of mortality and morbidity was observed in the two transplantation settings. Stimulation of MSC with exogenous tumor necrosis factor α and interferon (IFN)γ prior to infusion could not rescue BM-transplanted rats from lethal acute GVHD. In conclusion, repeated administrations of MSC failed to alleviate GVHD after fully or partially MHC-mismatched allo-SCT in the rat.