Mesenchymal Stromal Cells Fail to Prevent Acute Graft-versus-Host Disease and Graft Rejection after Dog-Leukocyte-Antigen Haploidentical Bone Marrow Transplantation

摘要

Mesenchymal stromal cells (MSC) have been shown to have immunosuppressive effects in vitro. To test the hypothesis that these effects can be harnessed to prevent graft-versus-host disease (GVHD) and graft rejection after hematopoietic cell transplantation (HCT), we administered a combination of three different immortalized marrow-derived MSC lines (15–30×10⁶ MSC/kg/day, 2–5 times/week) or third-party primary MSC (1.0×10⁶ MSC/kg/day, 3 times/week) to canine recipients (n=15) of dog-leukocyte antigen-haploidentical marrow grafts prepared with 9.2 Gy total body irradiation. Additional pharmacological immunosuppression was not given after HCT. Prior to their in vivo use, the MSC products were shown to suppress alloantigen-induced T cell proliferation in a dose-dependent, major histocompatibility complex-unrestricted and cell contact-independent fashion in vitro. Among 14 dogs evaluable, 7 (50%) rejected their grafts and 7 engrafted with ensuing rapidly fatal acute GVHD (50%). These observations were not statistically different from outcomes obtained with historical controls (n=11) not given MSC infusions (p=0.69). Hence, survival curves for MSC-treated dogs and controls were virtually superimposable (median survival, 18 vs. 15 days, respectively). Finally, outcomes of dogs given primary MSC (n=3) did not appear to be different from those given clonal MSC (n=12). In conclusion, our data fail to demonstrate MSC-mediated protection against GVHD and allograft rejection in this model.