Allogeneic bone marrow transplantation (BMT) is a treatment for many inherited diseases. Limitations to using BMT include toxicity associated with high doses of chemotherapy necessary to obtain engraftment, complications of graft-versus-host disease (GVHD), the scarcity of HLA matched donors, and concern about significant pre- and postnatal organ damage. In utero transplantation of hematopoietic stem cells (HSC) may overcome many of these limitations. An in utero HSC transplant model has been well-established in the rhesus monkey using parental T-cell depleted (TCD) bone marrow. HSC is directly injected into the fetal peritoneal cavity via ultrasound guidance. PCR of fetuses receiving transplants either on gestational day (GD) 40-45 (late first trimester) or GD 60-65 (early second trimester) has revealed similar engraftment rates. Donor cells were found in bone marrow, blood, spleen, and liver (in the fetal liver as early as 25 days post-transplant). GVHD has not occurred in any of the engrafted animals to 3 years follow-up. The tolerance of engrafted animals has been assessed using approaches such as the mixed lymphocyte reaction (MLR). No proliferative response of recipient cells to donor targets was noted, with a normal response observed to third party cells. The effectiveness of multiple in utero boosts after initial transplantation has also been evaluated. Fetuses initially transplanted ~GD 45 received either six boosts (every 10 days from GD 80-130), two boosts (GD 80 and 90), or one boost (GD 80). Liver and fetal blood samples collected with ultrasound guidance prenatally and at birth showed all animals to be engrafted in the liver on GD 80, and postnatally in the blood. These studies show that in rhesus macaques, TCD paternal bone marrow cells can durably engraft and may induce a state of tolerance in first or early second trimester fetal recipients. *KEY*Fetal transplantation, Hematopoietic stem cells, Engraftment
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