Very low levels of donor CD18+ neutrophils following allogeneic hematopoietic stem cell transplantation reverse the disease phenotype in canine leukocyte adhesion deficiency.
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.
Bauer
Thomas R
TR
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
Creevy
Kate E
KE
Gu
Yu-chen
YC
Tuschong
Laura M
LM
Donahue
Robert E
RE
Metzger
Mark E
ME
Embree
Lisa J
LJ
Burkholder
Tanya
T
Bacher
John D
JD
Romines
Chris
C
Thomas
Marvin L
ML
Colenda
Lyn
L
Hickstein
Dennis D
DD
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
D018821:CD18 Antigens; D004247:DNA