Fetal liver cell transplantation in dogs: results with DLA-compatible and incompatible grafts

We evaluated the ability of fetal liver hematopoietic cells to reconstitute hematopoiesis and immunity in lethally irradiated dogs. Nineteen consecutive dogs received transplants of fetal liver cells from donors identical or mismatched for DLA antigens. Six animals received 16 Gy fractionated total body irradiation (TBI) followed by transplantation of DLA-identical fetal liver. Three other dogs received transplants of fetal liver that was homozygous for a DLA haplotype shared by the recipient. No post-transplant immunosuppressive treatment was administered. All nine dogs had rapid and sustained restoration of hematopoiesis and none developed graft-versus-host disease. T and B-lymphocyte function recovered slowly over several months in all animals with sustained engraftment and they remained free of infection in open kennel conditions. These data indicate that a single DLA-identical fetal liver can reconstitute hematopoiesis in lethally irradiated dogs. This conditioning regimen was inadequate for transplantation of DLA-mismatched fetal liver cells; 6 of 6 dogs failed to engraft. We evaluated whether more intensive conditioning with 18 Gy fractionated TBI or 16 Gy TBI followed by post transplant treatment with methotrexate was feasible in 4 dogs. These regimens produced severe mucositis and gastrointestinal toxicity; 2 recipients of DLA-matched fetal liver transplants survived but 2 dogs receiving DLA-haploidentical fetal liver had engraftment but died of toxicity. Further studies are required to develop an effective, yet tolerable conditioning regimen in this setting. Fetal liver transplantation may ultimately be useful as a source of hematopoietic cells for transplantation in human patients if an effective conditioning regimen can be developed to allow engraftment of histoincompatible transplants.