Fetal immune suppression as adjunctive therapy for in utero hematopoietic stem cell transplantation in nonhuman primates.
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 > or = 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.
Shields
Laurence E
LE
Department of Obstetrics and Gynecology, Division of Perinatal Medicine, Box 356460, University of Washington, Seattle 98105-6460, USA. lshields@u.washington.edu
Gaur
Lakshmi
L
Delio
Patrick
P
Potter
Jennifer
J
Sieverkropp
Aimee
A
Andrews
Robert G
RG
D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000276:immunology; D001782:Blood Donors; D001805:Blood Transfusion, Intrauterine / Q000379:methods*; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005260:Female; D005333:Fetus / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008254:Macaca nemestrina; D008297:Male; D023421:Models, Animal; D011247:Pregnancy; D018183:Transplantation Chimera / Q000276:immunology*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D018952:Antigens, CD34; D007166:Immunosuppressive Agents