title: Chimerism and cure: hematologic and pathologic correction of murine sickle cell disease.
abstract: Bone marrow transplantation (BMT) is the only curative therapy for sickle cell disease (SCD). However, the morbidity and mortality related to pretransplantation myeloablative chemotherapy often outweighs the morbidity of SCD itself, thus severely limiting the number of patients eligible for transplantation. Although nonmyeloablative transplantation is expected to reduce the risk of BMT, it will likely result in mixed-chimerism rather than complete replacement with donor stem cells. Clinical application of nonmyeloablative transplantation thus requires knowledge of the effect of mixed chimerism on SCD pathophysiology. We have, therefore, created a panel of transplanted SCD mice that received transplants displaying an array of red blood cell (RBC) and white blood cell (WBC) chimerism. A significant enrichment of RBC over WBC chimerism occurred in these mice, because of the dramatic survival advantage of donor over sickle RBCs in the peripheral blood. Increasing levels of RBC chimerism provided progressive correction of hematologic and pathologic abnormalities. However, sickle bone marrow and splenic hematopoiesis was not corrected until peripheral blood sickle RBCs were fully replaced with donor RBCs. These results have important and unexpected implications for nonmyeloablative BMT for SCD. As the critical hematopoietic organs were not corrected without full RBC replacement, 100% peripheral blood RBC chimerism becomes the most important benchmark for cure after nonmyeloablative BMT.
authors.affiliation: Division of Hem/Onc/BMT, Department of Pediatrics, Emory University School of Medicine, 2040 Ridgewood Dr NE, Atlanta, GA 30322, USA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kean
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Manci
authors.forename: Jennifer
authors.initials: J
authors.lastname: Perry
authors.forename: Can
authors.initials: C
authors.lastname: Balkan
authors.forename: Shana
authors.initials: S
authors.lastname: Coley
authors.forename: David
authors.initials: D
authors.lastname: Holtzclaw
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Hsu
authors.forename: David R
authors.initials: DR
authors.lastname: Archer
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000473:pathology / Q000628:therapy*; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation; D002066:Busulfan; D002470:Cell Survival; D004195:Disease Models, Animal; D004906:Erythrocyte Count; D005914:Globins / Q000235:genetics; D006085:Graft Survival; D006410:Hematopoiesis; D006801:Humans; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D013154:Spleen / Q000473:pathology; D018183:Transplantation Chimera / Q000097:blood*; D019172:Transplantation Conditioning
chemical_list: D005914:Globins; D002066:Busulfan