title: Reduced efficacy of mesenchymal stromal cells in preventing graft-versus-host disease in an in vivo model of haploidentical bone marrow transplant with leukemia.
abstract: Mesenchymal stromal cell (MSC) immunosuppressive properties have been applied to treat graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplants (HSCTs). We have previously demonstrated that MSC infusions early after haplo-HSCT prevent GVHD in a haploidentical-HSCT mouse model. Now, we investigated the impact that MSCs' immunosuppressive properties have on the graft-versus-leukemia (GVL) effect. First, to mimic a chronic myeloid leukemia (CML) relapse after a haploidentical HSCT, lethally irradiated mice were coinfused with haploidentical donor bone marrow cells plus syngenic hematopoietic progenitors transduced with a retroviral vector encoding both the BCR/ABL oncogene and the ΔNGFR marker gene. As expected, a CML-like myeloproliferative syndrome developed in all the recipient animals. The addition of haploidentical splenocytes to the transplanted graft prevented CML development by a GVL effect, and all transplanted recipients died of GVHD. This GVL mouse model allowed us to investigate the impact of MSCs infused to prevent GVHD on days 0, 7, and 14 after HSCT, on the GVL effect, expecting an increase in leukemic relapse. Strikingly, a high mortality of the recipients was observed, caused by GVHD, and only few leukemic cells were detected in the recipient animals. In contrast, GVHD prevention by MSCs in the absence of BCR/ABL leukemic cells resulted in a significant survival of the recipients. In vitro data pointed to an inability of MSCs to control strong CTLs responses against BCR/ABL. Our results show that, although an evident increase in leukemic relapses induced by MSCs could not be detected, they showed a reduced efficacy in preventing GVHD that precluded us to draw clear conclusions on MSCs' impact over GVL effect.
authors.affiliation: Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Oviedo
authors.forename: Rosa
authors.initials: R
authors.lastname: Yañez
authors.forename: Isabel
authors.initials: I
authors.lastname: Colmenero
authors.forename: Montserrat
authors.initials: M
authors.lastname: Aldea
authors.forename: Antonio
authors.initials: A
authors.lastname: Rubio
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Bueren
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Lamana
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006238:Haploidy; D018380:Hematopoietic Stem Cell Transplantation; D007938:Leukemia / Q000097:blood / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012008:Recurrence; D012190:Retroviridae / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D016044:Fusion Proteins, bcr-abl