Long-term engraftment following in utero T cell-depleted parental marrow transplantation into fetal rhesus monkeys

M. J. Cowan, Alice F Tarantal, J. Capper, M. Harrison, M. Garovoy

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

A major concern with allogeneic BMT for treating most inherited diseases is the need to overcome graft rejection with conditioning chemotherapy which is associated with a relatively high morbidity and mortality. This can be eliminated if the transplant is done in utero when the fetus is unable to reject donor hematopoietic stem cells (HSC). We studied the efficacy of T cell-depleted (TCD) parental bone marrow as a source of HSC for transplantation into early gestation non-defective fetal rhesus monkeys. Thirteen opposite sexed TCD transplants were done into 44 day fetal recipients and 12 into 61 day recipients (165 day total gestation). The procedure-related mortality was 8%, all in the earlier age group. The overall survival was 60% at birth with a projected survival of 44 ± 10% at 1.5 years with no difference between the two age groups. We used a PCR assay for the rhesus Y chromosome to detect male donor cells in female recipients (six animals transplanted at 44 days and five at 63 days). The overall engraftment rate was 73% with no difference as a function of gestational age at transplant. In six long-term surviving engrafted females we detected donor cells in the peripheral blood and bone marrow up to 3 years of age. We found a delay in the appearance of donor cells in the peripheral blood in engrafted animals, in some cases for up to 6 months post-BMT. In vitro mixed lymphocyte reaction and cell-mediated lymphocytotoxicity studies between the recipient and donor cells indicate that tolerance was induced to donor cells. Individual and pooled erythroid and myeloid marrow colonies grown in methyl cellulose were collected and analyzed for donor origin by PCR. The amount of donor cells in marrows from long-term engrafted animals was < 0.1%. In a fetal recipient studied at 35 days post-BMT, donor cells were detected in bone marrow and liver in both erythroid and myeloid lineages. These results indicate that TCD parental marrow can durably engraft in utero. While the engraftment rate is similar to that seen with fetal liver as the source of HSC, the degree of peripheral blood engraftment (percent donor cells) in this non-defective primate model is low. It will require increasing the percent pre- or postnatally for this approach to be clinically relevant in those disorders in which there is no selective survival advantage for normal engrafted donor cells.

Original languageEnglish (US)
Pages (from-to)1157-1165
Number of pages9
JournalBone Marrow Transplantation
Volume17
Issue number6
StatePublished - Jun 1996

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Macaca mulatta
Transplantation
Bone Marrow
Tissue Donors
T-Lymphocytes
Hematopoietic Stem Cells
Transplants
Age Groups
Pregnancy
Polymerase Chain Reaction
Mixed Lymphocyte Culture Test
Methylcellulose
Survival
Mortality
Y Chromosome
Liver
Hematopoietic Stem Cell Transplantation
Graft Rejection
Primates
Gestational Age

Keywords

  • Fetus
  • In utero
  • Marrow transplantation
  • Rhesus monkeys
  • T cell depletion

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Long-term engraftment following in utero T cell-depleted parental marrow transplantation into fetal rhesus monkeys. / Cowan, M. J.; Tarantal, Alice F; Capper, J.; Harrison, M.; Garovoy, M.

In: Bone Marrow Transplantation, Vol. 17, No. 6, 06.1996, p. 1157-1165.

Research output: Contribution to journalArticle

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