A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex-mismatched bone marrow transplantation.
The morbidity and mortality associated with sickle cell disease (SCD) is caused by hemolytic anemia, vaso-occlusion, and progressive multiorgan damage. Bone marrow transplantation (BMT) is currently the only curative therapy; however, toxic myeloablative preconditioning and barriers to allotransplantation limit this therapy to children with major SCD complications and HLA-matched donors. In trials of myeloablative BMT designed to yield total marrow replacement with donor stem cells, a subset of patients developed mixed chimerism. Importantly, these patients showed resolution of SCD complications. This implies that less toxic preparative regimens, purposefully yielding mixed chimerism after transplantation, may be sufficient to cure SCD without the risks of myeloablation. To rigorously test this hypothesis, we used a murine model for SCD to investigate whether nonmyeloablative preconditioning coupled with tolerance induction could intentionally create mixed chimerism and a clinical cure. We applied a well-tolerated, nonirradiation-based, allogeneic transplantation protocol using nonmyeloablative preconditioning (low-dose busulfan) and costimulation blockade (CTLA4-Ig and anti-CD40L) to produce mixed chimerism and transplantation tolerance to fully major histocompatibility complex-mismatched donor marrow. Chimeric mice were phenotypically cured of SCD and had normal RBC morphology and hematologic indices (hemoglobin, hematocrit, reticulocyte, and white blood cell counts) without evidence of graft versus host disease. Importantly, they also showed normalization of characteristic spleen and kidney pathology. These experiments demonstrate the ability to produce a phenotypic cure for murine SCD using a nonmyeloablative protocol with fully histocompatibility complex-mismatched donors. They suggest a future treatment strategy for human SCD patients that reduces the toxicity of conventional BMT and expands the use of allotransplantation to non-HLA-matched donors.
Kean
Leslie S
LS
Division of Hematology, Oncology Blood and Marrow Transplantation, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Durham
Megan M
MM
Adams
Andrew B
AB
Hsu
Lewis L
LL
Perry
Jennifer R
JR
Dillehay
Dirck
D
Pearson
Thomas C
TC
Waller
Edmund K
EK
Larsen
Christian P
CP
Archer
David R
DR
D000069594:Abatacept; D000755:Anemia, Sickle Cell / Q000150:complications / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000633:toxicity; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods*; D002066:Busulfan / Q000008:administration & dosage / Q000633:toxicity; D023201:CD40 Ligand / Q000276:immunology; D060908:CTLA-4 Antigen; D006648:Histocompatibility; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D051379:Mice; D013154:Spleen / Q000187:drug effects; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods*; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous / Q000276:immunology / Q000379:methods; D016896:Treatment Outcome
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D000069594:Abatacept; D002066:Busulfan