Riley John S, McClain Lauren E, Stratigis John D, Coons Barbara E, Ahn Nicholas J, Li Haiying, Loukogeorgakis Stavros P, Fachin Camila G, Dias Andre I B S, Flake Alan W, Peranteau William H
Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, PA.
Blood Adv. 2020 Mar 24;4(6):1102-1114. doi: 10.1182/bloodadvances.2019001208.
In utero hematopoietic cell transplantation (IUHCT) has the potential to cure congenital hematologic disorders including sickle cell disease. However, the window of opportunity for IUHCT closes with the acquisition of T-cell immunity, beginning at approximately 14 weeks gestation, posing significant technical challenges and excluding from treatment fetuses evaluated after the first trimester. Here we report that regulatory T cells can promote alloengraftment and preserve allograft tolerance after the acquisition of T-cell immunity in a mouse model of late-gestation IUHCT. We show that allografts enriched with regulatory T cells harvested from either IUHCT-tolerant or naive mice engraft at 20 days post coitum (DPC) with equal frequency to unenriched allografts transplanted at 14 DPC. Long-term, multilineage donor cell chimerism was achieved in the absence of graft-versus-host disease or mortality. Decreased alloreactivity among recipient T cells was observed consistent with donor-specific tolerance. These findings suggest that donor graft enrichment with regulatory T cells could be used to successfully perform IUHCT later in gestation.
宫内造血细胞移植（IUHCT）有治愈包括镰状细胞病在内的先天性血液系统疾病的潜力。然而，IUHCT的机会窗口随着T细胞免疫的获得而关闭，大约在妊娠14周时开始，这带来了重大技术挑战，并将孕早期后评估的胎儿排除在治疗之外。在此，我们报告在晚期妊娠IUHCT小鼠模型中，调节性T细胞可在获得T细胞免疫后促进同种异体移植并维持同种异体移植耐受性。我们表明，从IUHCT耐受或未接触过抗原的小鼠中收获的富含调节性T细胞的同种异体移植物在交配后20天（DPC）植入，频率与在14 DPC移植的未富集同种异体移植物相同。在没有移植物抗宿主病或死亡的情况下实现了长期、多谱系供体细胞嵌合。观察到受体T细胞之间的同种异体反应性降低，这与供体特异性耐受性一致。这些发现表明，用调节性T细胞富集供体移植物可用于在妊娠后期成功进行IUHCT。
