title: Very low levels of donor CD18+ neutrophils following allogeneic hematopoietic stem cell transplantation reverse the disease phenotype in canine leukocyte adhesion deficiency.
abstract: Children with the severe phenotype of the genetic immunodeficiency disease leukocyte adhesion deficiency or LAD experience life-threatening bacterial infections because of molecular defects in the leukocyte integrin CD18 molecule and the resultant failure to express the CD11/CD18 adhesion molecules on the leukocyte surface. Hematopoietic stem cell transplantation remains the only definitive therapy for LAD; however, the degree of donor chimerism and particularly the number of CD18(+) donor-derived neutrophils required to reverse the disease phenotype are not known. We performed nonmyeloablative hematopoietic stem cell transplantations from healthy matched littermates in 9 dogs with the canine form of LAD known as CLAD and demonstrate that in the 3 dogs with the lowest level of donor chimerism, less than 500 CD18(+) donor-derived neutrophils/microL in the peripheral blood of the CLAD recipients resulted in reversal of the CLAD disease phenotype. These results demonstrate the value of a disease-specific, large-animal model for identifying the lowest therapeutic level required for successful cellular and gene therapy.
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 12C-116, 10 Center Dr, MSC1907, Bethesda, MD 20892-1907, USA. bauert@mail.nih.gov
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bauer
authors.forename: Kate E
authors.initials: KE
authors.lastname: Creevy
authors.forename: Yu-chen
authors.initials: YC
authors.lastname: Gu
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tuschong
authors.forename: Robert E
authors.initials: RE
authors.lastname: Donahue
authors.forename: Mark E
authors.initials: ME
authors.lastname: Metzger
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Embree
authors.forename: Tanya
authors.initials: T
authors.lastname: Burkholder
authors.forename: John D
authors.initials: JD
authors.lastname: Bacher
authors.forename: Chris
authors.initials: C
authors.lastname: Romines
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Thomas
authors.forename: Lyn
authors.initials: L
authors.lastname: Colenda
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000032:analysis*; D004247:DNA / Q000032:analysis; D004283:Dog Diseases; D004285:Dogs; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D007958:Leukocyte Count; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000097:blood / Q000628:therapy*; D009504:Neutrophils / Q000166:cytology*; D010641:Phenotype; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D018821:CD18 Antigens; D004247:DNA