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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3960-3965
RED CELLS
Effects of mixed hematopoietic chimerism in a mouse model of bone
marrow transplantation for sickle cell anemia
Robert Iannone,
Leo Luznik,
Laura W. Engstrom,
Sherrie L. Tennessee,
Frederic B. Askin,
James F. Casella,
Thomas S. Kickler,
Steven N. Goodman,
Anita L. Hawkins,
Constance A. Griffin,
Lori Noffsinger, and
Ephraim J. Fuchs
From the Departments of Pediatrics, Pathology, and
Oncology, Johns Hopkins Hospital and Oncology Center, Baltimore, MD.
Sickle cell anemia (SCA) is an inherited disorder of  -globin,
resulting in red blood cell rigidity, anemia, painful crises, organ
infarctions, and reduced life expectancy. Allogeneic blood or marrow
transplantation (BMT) can cure SCA but is associated with an 8% to
10% mortality rate, primarily from complications of marrow-ablative
conditioning. Transplantation of allogeneic marrow after less intensive
conditioning reduces toxicity but may result in stable mixed
hematopoietic chimerism. The few SCA patients who inadvertently
developed mixed chimerism after BMT remain symptom free, suggesting
that mixed chimerism can reduce disease-related morbidity. However,
because the effects of various levels of mixed chimerism on organ
pathology have not been characterized, this study examined the
histologic effects of an increasing percentage of normal donor
hematopoiesis in a mouse model of BMT for SCA. In lethally irradiated
normal mice that were reconstituted with varying ratios of
T-cell-depleted marrow from normal and transgenic "sickle cell"
mice, normal myeloid chimerism in excess of 25% was associated with
more than 90% normal hemoglobin (Hb). However, 70% normal myeloid
chimerism was required to reverse the anemia. Organ pathology,
including liver infarction, was present in mice with sickle Hb (HbS)
levels as low as 16.8% (19.6% normal myeloid chimerism). Histologic
abnormalities increased in severity up to 80% HbS, but were less
severe in mice with more than 80% HbS than in those with 40% to 80%
HbS. Therefore, stable mixed chimerism resulting from
nonmyeloablative BMT may reduce the morbidity from SCA, but
prevention of all disease complications may require minimizing the fraction of circulating sickle red cells.
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