Effects of mixed hematopoietic chimerism in a mouse model of bone marrow transplantation for sickle cell anemia

Robert Lannone, 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, Ephraim J. Fuchs

Research output: Contribution to journalArticle

Abstract

Sickle cell anemia (SCA) is an inherited disorder of β-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 marrowablative 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.

Original languageEnglish (US)
Pages (from-to)3960-3965
Number of pages6
JournalBlood
Volume97
Issue number12
DOIs
StatePublished - Jun 15 2001

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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