|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 March 2002, Vol. 99, No. 5, pp. 1840-1849
TRANSPLANTATION
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
Leslie S. Kean,
Megan M. Durham,
Andrew B. Adams,
Lewis L. Hsu,
Jennifer R. Perry,
Dirck Dillehay,
Thomas C. Pearson,
Edmund K. Waller,
Christian P. Larsen, and
David R. Archer
From the Division of Hematology, Oncology Blood
and Marrow Transplantation, Department of Pediatrics; Transplant
Immunology Laboratory, Department of Surgery; Department of Medicine;
and Division of Animal Resources and Department of Pathology; all of
Emory University School of Medicine, Atlanta, GA.
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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
B. H. Koehn, M. A. Williams, K. Borom, S. Gangappa, T. C. Pearson, R. Ahmed, and C. P. Larsen
Fully MHC-Disparate Mixed Hemopoietic Chimeras Show Specific Defects in the Control of Chronic Viral Infections
J. Immunol.,
August 15, 2007;
179(4):
2616 - 2626.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. E. Richard, M. Weinreich, K.-H. Chang, J. Ieremia, M. M. Stevenson, and C. A. Blau
Modulating erythrocyte chimerism in a mouse model of pyruvate kinase deficiency
Blood,
June 15, 2004;
103(12):
4432 - 4439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. S. Kean, E. A. Manci, J. Perry, C. Balkan, S. Coley, D. Holtzclaw, A. B. Adams, C. P. Larsen, L. L. Hsu, and D. R. Archer
Chimerism and cure: hematologic and pathologic correction of murine sickle cell disease
Blood,
December 15, 2003;
102(13):
4582 - 4593.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Blaha, S. Bigenzahn, Z. Koporc, M. Schmid, F. Langer, E. Selzer, H. Bergmeister, F. Wrba, J. Kurtz, C. Kiss, et al.
The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade
Blood,
April 1, 2003;
101(7):
2886 - 2893.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. E. Phillips, T. G. Markees, J. P. Mordes, D. L. Greiner, and A. A. Rossini
Blockade of CD40-Mediated Signaling Is Sufficient for Inducing Islet But Not Skin Transplantation Tolerance
J. Immunol.,
March 15, 2003;
170(6):
3015 - 3023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Williams, A. B. Adams, M. B. Walsh, N. Shirasugi, T. M. Onami, T. C. Pearson, R. Ahmed, and C. P. Larsen
Primary and Secondary Immunocompetence in Mixed Allogeneic Chimeras
J. Immunol.,
March 1, 2003;
170(5):
2382 - 2389.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
