FETAL BLOOD DEVELOPMENT MICROENVIRONMENTAL ASPECTS

Project: Research project

Description

Sickle cell anemia and thalassemia are hemoglobinopathies associated with
severe morbidity and mortality. No curative treatment is readily available
for these patients. Recent advances in the prenatal diagnoses of these
disorders permit the early identification of affected fetuses. However,
the only intervention possible to date has been abortion of the fetus.
Fetal transplantation of normal adult marrow in utero could correct these
life-threatening disorders and offer an alternative to aborting affected
fetuses. To accomplish this goal, techniques must be developed for fetal
transplantation in man. However, little information is available about the
growth of adult hematopoietic cells in a fetal environment. In this
proposal, we will transplant baboon adult marrow cells into baboon fetuses
at different gestational stages to determine: 1) Whether adult to fetal
marrow transplantation is feasible in primates; 2) whether adult
hematopoietic cells can grow in fetal liver, spleen, and marrow or can only
grow in the marrow; and 3) whether adult marrow cells transplanted into a
fetal microenvironment express an adult or fetal phenotype. In the first
phase of these studies, 20 fetuses will be transplanted at different
gestational ages and 28 days later, donor cells will be identified in cell
suspensions of fetal liver, spleen and marrow using the genetic
polymorphism we have recently demonstrated in baboons at the glucose
phosphate isomerase (GPI) locus. We will also determine if donor
hematopoietic progenitor cells are present in these organs using in vitro
cultures of erythroid (CFU-E, BFU-E) and multipotent (CFU-GEMM) progenitor
cells. The colonies will be tested for the presence of donor cells by
means of GPI isozymes and the phenotype of the colonies assessed by
analyzing the profile of surface membrane glycoproteins and expression of
adult or fetal type hemoglobin. After determining the optimum fetal age
for adult marrow engraftment, we will transplant 10 animals and "sham
transplant" 5 control animals. Hematologic chimerism will be determined in
vivo using GPI determinations of peripheral blood cells. The presence of
graft versus host disease will be determined and graded histologically.
Surviving animals transplanted in the second phase of these studies will be
followed for one year to determine if chimerism persists and the natural
history of graft verus host disease.
StatusFinished
Effective start/end date4/1/8511/30/88

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Fetal Development
Fetal Blood
Bone Marrow
Glucose-6-Phosphate Isomerase
Papio
Erythroid Precursor Cells
Chimerism
Fetus
Membrane Glycoproteins
Transplants
Spleen
Transplantation
Tissue Donors
Myeloid Progenitor Cells
Phenotype
Fetal Hemoglobin
Hemoglobinopathies
Thalassemia
Liver
Sickle Cell Anemia

ASJC

  • Medicine(all)