title: Haploidentical in utero hematopoietic cell transplantation improves phenotype and can induce tolerance for postnatal same-donor transplants in the canine leukocyte adhesion deficiency model.
abstract: In the murine model, in utero hematopoietic cell transplantation (IUHCT) has been shown to achieve low levels of allogeneic chimerism and associated donor-specific tolerance permitting minimal conditioning postnatal hematopoietic stem cell transplantation (HSCT). In this pilot study, we investigated IUHCT in the canine leukocyte adhesion deficiency (CLAD) model. Haploidentical IUHCT resulted in stable low-level donor cell chimerism in all dogs that could be analyzed by sensitive detection methodology (4 of 10) through 18 months of follow-up. In the 2 CLAD recipients, low-level chimerism resulted in amelioration and complete reversal of the CLAD phenotype, respectively. Six recipients of IUHCT (5 carriers and 1 CLAD) subsequently received postnatal HSCT from the same haploidentical prenatal donor after minimal conditioning with busulfan 10 mg/kg. Chimerism in 2 of 5 CLAD carriers that underwent HSCT increased from < 1% pre-HSCT to sustained levels of 35% to 45%. Control animals undergoing postnatal haploidentical HSCT without IUHCT had no detectable donor chimerism. These results demonstrate that haploidentical IUHCT in the CLAD model can result in low-level donor chimerism that can prevent the lethal phenotype in CLAD dogs, and can result in donor-specific tolerance that can facilitate postnatal minimal conditioning HSCT.
authors.affiliation: Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Peranteau
authors.forename: Todd E
authors.initials: TE
authors.lastname: Heaton
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Gu
authors.forename: Susan W
authors.initials: SW
authors.lastname: Volk
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bauer
authors.forename: Keith
authors.initials: K
authors.lastname: Alcorn
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tuschong
authors.forename: Mark P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
authors.forename: Alan W
authors.initials: AW
authors.lastname: Flake
mesh_terms: D000818:Animals; D002066:Busulfan / Q000008:administration & dosage; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D046128:Fetal Therapies / Q000379:methods*; D006086:Graft vs Host Disease / Q000276:immunology; D006238:Haploidy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000276:immunology / Q000628:therapy*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D011247:Pregnancy; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007166:Immunosuppressive Agents; D002066:Busulfan