Fetal Immune Suppression as Adjunctive Therapy for In Utero Hematopoietic Stem Cell Transplantation in Nonhuman Primates

Abstract

In utero hematopoietic stem cell transplantation could potentially be used to treat many genetic diseases but rarely has been successful except in severe immunodeficiency syndromes. We explored two ways to potentially increase chimerism in a nonhuman primate model: (a) fetal immune suppression at the time of transplantation and (b) postnatal donor stem cell infusion. Fetal Macaca nemestrina treated with a combination of the corticosteroid betamethasone (0.9 mg/kg) and rabbit thymoglobulin (ATG; 50 mg/kg) were given haploidentical, marrow‐derived, CD34+‐enriched donor cells. Animals treated postnatally received either donor‐derived T cell–depleted or CD34+‐enriched marrow cells. Chimerism was determined by traditional and real‐time polymerase chain reaction from marrow, marrow progenitors, peripheral blood, and mature peripheral blood progeny. After birth, the level of chimerism in the progenitor population was higher in the immune‐suppressed animals relative to controls (11.3% ± 2.7% and 5.1% ± 1.5%, respectively; p = .057). Chimerism remained significantly elevated in both marrow (p = .02) and fluorescence‐activated cell sorted and purified CD34+ cells (p = .01) relative to control animals at ≥ 14 months of age. Peripheral blood chimerism, both at birth and long term, was similar in immune‐suppressed and control animals. In the animals receiving postnatal donor cell infusions, there was an initial increase in progenitor chimerism; however, at 6‐month follow‐up, the level of chimerism was unchanged from the preinfusion values. Although fetal immune suppression was associated with an increase in the level of progenitor and marrow chimerism, the total contribution to marrow and the levels of mature donor progeny in the peripheral blood remained low. The level of long‐term chimerism also was not improved with postnatal donor cell infusion.

Comparison of Growth and Differentiation of Fetal and Adult Rhesus Monkey Mesenchymal Stem Cells

“…Nonhuman primates have similar stem and progenitor cell dynamics when compared to humans and have been invaluable in developing and assessing new therapeutic transplant approaches for the treatment of human diseases (16)(17)(18)(19). Studies with nonhuman primates that have focused on hematopoietic stem cell (HSC) transplantation and gene marking indicate outcomes that closely parallel those from human clinical trials (16,20).…”

Advances in fetal therapy

“…However, successful intrauterine haematopoietic stem cell transplants have only been achieved in the immunodeficient fetus, suggesting that there may still be an immunological barrier. Studies have shown an allogenic response from 9–12 weeks of gestation, the magnitude of response increasing with gestational age, 18 adding weight to the theory that failure in the non‐immunodeficient fetus may be due to graft‐versus‐host reaction as reported in animal models 19 . Human leukocyte antigen compatibility may thus be important in the success of fetal stem cell transplantation.…”

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

“…In the absence of immunosuppression, only microchimerism has been achieved in human fetal recipients or nonhuman primate models of IUHCT. [1][2][3][4][5][6] These levels are too low for the correction of most diseases and have not been demonstrated to predict tolerance. The reasons for this failure are unclear and reflect a limited understanding of the engraftment barriers involved in clinical IUHCT.…”