A murine model of graft-vs-host disease after in utero hematopoietic cell transplantation

PurposeGraft-vs-host disease (GvHD) is a known complication of in utero bone marrow transplantation. However, GvHD has been difficult to study owing to frequent fetal demise. We describe the first consistent murine model of GvHD with postnatal survival after in utero hematopoietic cell transplantation.MethodsA 50/50 mixture of bone marrow and splenocytes (106) from 6-week-old C57/BL6 (H2-b) mice was injected intraperitoneally into Balb/c (H2-d) fetuses at e14 to 16. Live born pups were followed for clinical GvHD. Peripheral blood and hematopoietic organ chimerism was confirmed by flow cytometry and polymerase chain reaction. Organ samples were isolated for histology.ResultsTwenty-seven (75%) of 36 surviving pups displayed clinical GvHD by 2 weeks compared with 9 developmentally normal pups. Mean difference in weight between the 2 groups was 2.9 g at 7 days and 5.2 g at 14 days of life (P < .0001). All 27 pups with clinical GvHD and 1 normal-appearing pup had blood chimerism ranging from 1.5% to 65%. Eight of the 9 normal-appearing pups had 0% chimerism. Histologic analysis revealed findings of GvHD in liver, spleen, small intestine, and skin specimens of only chimeric pups.ConclusionsA consistent murine model of GvHD can be achieved after in utero transplantation of major histocompatibility complex–mismatched bone marrow and splenocytes. Future studies will use this model to examine approaches to prevent GvHD after in utero stem cell transplantation.