Children's Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Pediatric Surgery, Washington University in St. Louis, St. Louis, Missouri.
Children's Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Biol Blood Marrow Transplant. 2018 Sep;24(9):1795-1801. doi: 10.1016/j.bbmt.2018.05.020. Epub 2018 May 23.
In utero hematopoietic cell transplantation (IUHCT) offers the potential to achieve allogeneic engraftment and associated donor-specific tolerance without the need for toxic conditioning, as we have previously demonstrated in the murine and canine models. This strategy holds great promise in the treatment of many hematopoietic disorders, including the hemoglobinopathies. Graft-versus-host disease (GVHD) represents the greatest theoretical risk of IUHCT and has never been characterized in the context of IUHCT. We recently described a preclinical canine model of IUHCT, allowing further study of the technique and its complications. We aimed to establish a threshold T cell dose for IUHCT-induced GVHD in the haploidentical canine model and to define the GVHD phenotype. Using a range of T cell concentrations within the donor inoculum, we were able to characterize the phenotype of IUHCT-induced GVHD and establish a clear threshold for its induction between 3% and 5% graft CD3 cell content. Given the complete absence of GVHD at CD3 doses of 1% to 3% and the excellent engraftment with the lowest dose, there is a safe therapeutic index for a clinical trial of IUHCT.
子宫内造血细胞移植（IUHCT）提供了实现同种异体植入和相关供体特异性耐受的潜力，而无需进行毒性调理，正如我们之前在小鼠和犬模型中所证明的那样。这种策略在治疗许多血液疾病方面具有很大的潜力，包括血红蛋白病。移植物抗宿主病（GVHD）是 IUHCT 最大的理论风险，在 IUHCT 的背景下从未得到过描述。我们最近描述了 IUHCT 的临床前犬模型，从而可以进一步研究该技术及其并发症。我们旨在确定半相合犬模型中 IUHCT 诱导的 GVHD 的 T 细胞剂量阈值，并定义 GVHD 表型。使用供体接种物中一系列 T 细胞浓度，我们能够描述 IUHCT 诱导的 GVHD 的表型，并确定其诱导的明确阈值为 3%至 5%移植物 CD3 细胞含量。鉴于在 CD3 剂量为 1%至 3%时完全没有 GVHD，并且最低剂量具有出色的植入效果，因此 IUHCT 临床试验具有安全的治疗指数。
