title: Nonmyeloablative conditioning with busulfan before matched littermate bone marrow transplantation results in reversal of the disease phenotype in canine leukocyte adhesion deficiency.
abstract: Leukocyte adhesion deficiency (LAD)-1, a primary immunodeficiency disease caused by molecular defects in the leukocyte integrin CD18 molecule, is characterized by recurrent, life-threatening bacterial infections. Myeloablative hematopoietic stem cell transplantation is the only curative treatment for LAD-1. Recently, canine LAD (CLAD) has been shown to be a valuable animal model for the preclinical testing of nonmyeloablative transplantation regimens for the treatment of children with LAD-1. To develop new allogeneic transplantation approaches for LAD-1, we assessed a nonmyeloablative conditioning regimen consisting of busulfan as a single agent before matched littermate allogeneic bone marrow transplantation in CLAD. Three CLAD dogs received busulfan 10 mg/kg intravenously before infusion of matched littermate bone marrow, and all dogs received posttransplantation immunosuppression with cyclosporin A and mycophenolate mofetil. Initially, all 3 dogs became mixed chimeras, and levels of donor chimerism sufficient to reverse the CLAD phenotype persisted in 2 animals. The third dog maintained donor microchimerism with an attenuated CLAD phenotype. These 3 dogs have all been followed up for at least 1 year after transplantation. These results indicate that a nonmyeloablative conditioning regimen with chemotherapy alone is capable of generating stable mixed chimerism and reversal of the disease phenotype in CLAD.
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. sokolicr@mail.nih.gov
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sokolic
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bauer
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Gu
authors.forename: Mehreen
authors.initials: M
authors.lastname: Hai
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tuschong
authors.forename: Tanya
authors.initials: T
authors.lastname: Burkholder
authors.forename: Lyn
authors.initials: L
authors.lastname: Colenda
authors.forename: John
authors.initials: J
authors.lastname: Bacher
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002066:Busulfan / Q000008:administration & dosage*; D016572:Cyclosporine / Q000008:administration & dosage; D004283:Dog Diseases / Q000628:therapy; D004285:Dogs; D005500:Follow-Up Studies; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000401:mortality / Q000628:therapy*; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D010641:Phenotype; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D002066:Busulfan; D009173:Mycophenolic Acid