In Utero Hematopoietic Stem Cell Transplantation in Nonhuman Primates: The Role of T Cells

Abstract

In utero transplantation of hematopoietic stem cells is a promising treatment for immune and hematologic diseases of fetuses and newborns. Unfortunately, there are limited data from nonhuman primates and humans describing optimal transplantation conditions. The purpose of this investigation was to determine the effect of T-cell number on engraftment and the level of chimerism after in utero transplantation in nonhuman primates. CD34 + allogeneic adult bone marrow cells, obtained from the sire after G-CSF and stem cell factor administration, were transplanted into female fetal recipients. The average CD34 + cell dose was 3.0 × 10 9 /kg (range, 9.9 × 10 8 to 4.4 × 10 9 ) and the T-cell dose ranged from 2.6 × 10 5 to 1.1 × 10 8 /kg. Chimerism was determined in peripheral blood subsets (CD2, CD13, and CD20) and in progenitor cell populations by using polymerase chain reaction. Chimerism was noted in seven of eight live-born animals. The level of chimerism in the progenitor population was related to the fetal T-cell dose (r = 0.64, p < 0.02). At the lowest T-cell dose (2.6 × 10 5 /kg), no chimerism was detected. As the T-cell dose increased to 10 6-7 /kg, the level of chimerism increased. Adjusting the T-cell dose to 1.1 × 10 8 /kg resulted in fatal graft-versus-host disease (GVHD). The results of this study emphasize the importance of T cells in facilitating donor cell engraftment and in producing GVHD in fetal nonhuman primates. Some animals achieved levels of chimerism in the marrow hematopoietic progenitor cell population that would likely have clinical relevance. However, the levels of chimerism in peripheral blood were too low for therapeutic benefit. Further studies are needed to test methods that are likely to enhance donor cell engraftment and peripheral blood levels of donor cells.