Transplantation of a fetus with paternal Thy-1+CD34+cells for chronic granulomatous disease

Abstract

Summary:A fetus diagnosed with X-linked chronic granulomatous disease was transplanted with Thy-1 ؉ CD34 ؉ cells of paternal origin. The transplant was performed at 14 weeks gestation by ultrasound guided injection into the peritoneal cavity. The fetus was delivered at 38 weeks gestation after an otherwise uneventful pregnancy. Umbilical cord blood was collected and used to determine the level of peripheral blood chimerism as well as levels of functional engrafted cells. Flow cytometry was used to detect donor leukocytes identified as HLA-A2 ؊ B7 ؉ cells, whereas recipient cells were identified as HLA-A2 ؉ B7 ؊ cells. No evidence of donor cell engraftment above a level of 0.01% was found. PCR was used to detect HLA-DRB1*15 ؉ donor cells among the recipient's HLA-DRB1*15 ؊ cells, but no engraftment was seen with a sensitivity of 1:1000. The presence of functional, donor-derived neutrophils was assessed by flow cytometry using two different fluorescent dyes that measure reactive oxygen species generated by the phagocyte NADPH oxidase. No evidence of paternal-derived functional neutrophils above a level of 0.15% was observed. Peripheral blood and bone marrow samples were collected at 6 months of age. Neither sample showed engraftment by HLA typing using both flow cytometry and PCR. Functional phagocytes were also not observed. Furthermore, no indication of immunological tolerance specific for the donor cells was indicated by a mixed lymphocyte reaction assay performed at 6 months of age. While there appears to be no engraftment of the donor stem cells, the transplant caused no harm to the fetus and the child was healthy at 6 months of age. Analyses of fetal tissues, obtained from elective abortions, revealed that CD3 ؉ T cells and CD56 ؉ CD3 ؊ NK cells are present in the liver at 8 weeks gestation and in the blood by 9 weeks gestation. The presence of these lymphocytes may contribute to the

A murine model of graft-vs-host disease after in utero hematopoietic cell transplantation

“…Wakabayashi et al [14] showed that GvHD also occurs in human tissue after bone marrow transplantation, particularly in areas that are not highly populated by dendritic cells. Through human cases of in utero HSCT, it is now known that the incidence of GvHD in in utero transplant models can be minimized by T-cell depletion [8,[15][16][17][18][19]. However, this comes at the expense of decreased donor cell engraftment [8,19].…”

Prevention of Graft Rejection by Donor Type II CD8⁺ T Cells (Tc2 Cells) Is Not Sufficient to Improve Engraftment in Fetal Transplantation

“…A number of lines of evidence point toward a lack of space in the hematopoietic tissues for donor HSCs to engraft as one possible reason for poor outcomes [1,10]. Despite the immaturity of the fetal immune system, NK cells and even T cells are present in the late first trimester fetus and may further prevent donor cell engraftment [11]. Better defining the barriers to HSC engraftment in utero is the key to improving IUT, to treat a wider range of birth defects.…”

Ontogenic changes in CD95 expression on human leukocytes: prevalence of T-cells expressing activation markers and identification of CD95−CD45RO+ T-cells in the fetus

“…Nonetheless, the cellular immune system begins its development early in gestation around the end of the first trimester. Reports suggest that T cells can be found in liver and peripheral blood as early as 7 and 9 weeks' gestation, respectively, although their overall numbers are very low [1,2]. Intrathymic CD3…”