Elsevier

The Lancet

Volume 348, Issue 9040, 30 November 1996, Pages 1484-1487
The Lancet

Early Report
In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDX1)

https://doi.org/10.1016/S0140-6736(96)09392-0Get rights and content

Summary

Background

X-linked severe combined immunodeficiency (SCIDX1) is an inherited immune defect which leads to death in infancy from severe infections. The defect is caused by mutations of the IL-2RG gene that encodes for the common γ chain shared by several cytokine receptors. The disease is characterised by lack of T and NK cells with normal numbers of B cells. SCIDX1 can be cured by bone marrow transplantation (BMT) or prevented by abortion after prenatal diagnosis.

Methods

A male fetus was diagnosed as having SCIDX1 by molecular, immunophenotypic, and functional analyses. The fetus was injected intraperitoneally under ultrasound guidance with CD34 haematopoietic progenitor cells purified from paternal bone marrow and T-cell depleted by E resetting. Chimerism analysis was by HLA-DQα typing and γ-chain staining on cord blood.

Findings

A healthy 3·6 kg boy was delivered by caesarean section at 38 weeks of gestation with no clinical or laboratory signs of graft-versus-host disease. Engraftment of donor-derived CD2 cells was found at birth. At 3·5 months of age the infant is well and his T-cell counts and function are normal.

Interpretation

In-utero transplantation of haematopoietic progenitor cells allowed immune reconstitution of a fetus with SCIDXI and may be an alternative to elective abortion. Our report should encourage applications of this method to other inherited disorders curable by BMT.

Introduction

X-linked severe combined immunodeficiency (SCIDX1) is the predominant form of SCID; in which there is a lack of T and NK cells with a normal or increased number of B lymphocytes.1 SCIDX1 is caused by mutations of the IL-2RG gene that encodes for the common γ chain shared by several interleukin receptors.2

The disease is fatal unless cured by bone-marrow transplantation (BMT). The best results are achieved with HLA-identical donors (97%), whereas HLA haploidentical family donors result in lower success rates (52%). Prevention of the disease is based on genetic counselling, prenatal diagnosis by mutation analysis of chononic villi,3 or immunological evaluation of fetal blood.4 After diagnosis of SCIDX1 in a fetus, the only alternative to the birth of an affected infant is elective abortion.

An alternative to postnatal BMT has been suggested: to do BMT in utero, when the haematopoietic system is still developing and might be overcome by donor haematopoietic stem cells.5 The immune system is immature early in pregnancy and might allow donor cells to be tolerated.6 Rhesus monkey fetal liver cells7 and T-cell depleted bone marrow8 have been transplanted successfully into fetal rhesus monkeys at 40 to 60 days gestation (length of gestation is 165 days) with long-term engraftment. Xenogenic HLA barriers can also be overcome without graft-versus-host disease (GvHD) if human CD34 cells are transplanted into fetal sheep in utero at 50 days of gestation (length of gestation is 150 days).9 Genetic defects in mice such as moderate anaemia10 and severe combined immunodeficiency SCID11 have been successfully treated by in-utero transplantation of haematopoietic stem cells.

Although in-utero transplantation after the 16th week of gestation is often unsuccessful in human beings,12, 13 primary immunodeficiences represent ideal disease candidates for this treatment, because graft rejection is unlikely. Flake14 has reported preliminary evidence for successful in-utero transplantation in a fetus with SCIDX1. We report here in-utero haematopoietic stem-cell transplantation and rescue of an affected male fetus with SCIDX1 (figure 1).

Section snippets

Methods

The affected fetus was from a couple, who had previously lost a male infant with SCIDX1 while the infant waited for BMT. During the second pregnancy, X-chromosome inactivation analysis showed that the mother was a carrier of SCIDX1. At the 20th week of gestation the mother had an amniocentesis, and prenatal diagnosis showed an affected boy. The parents refused elective abortion and were worried about post-natal BMT. 1 week later, after approval by the local ethics committee, positively selected

Maternal X-inactivation analysis

The CD4 fraction showed non-random X-chromosomal inactivation (one band) after Hpa II digestion and PCR amplification at the human androgen receptor (HUMARA) locus. The undigested sample showed two bands. The same pattern of X-chromosomal inactivation was observed in the CD4 fraction, defined as cells remaining after Ficoll density centrifugation, and cell adherence to plastic then depletion of CD4 cells with anti-CD4 coated magnetic beads. Neutrophils served as a tissue-specific control,

Discussion

We successfully treated a fetus with SCIDX1 with in-utero transplantation of paternally derived haematopoietic progenitor cells. Our protocol with use of multiple intraperitoneal injections was based on the results obtained in animal models.9 At birth, T and NK cells were detectable, and their number increased progressively during the following months. These cell populations are low or missing in males affected with SCIDX1, and carrier women show non-random inactivation of the mutated X

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    In-utero transplantation of fetal liver hematopoietic stem cells in monkeys

    Lancet

    (1989)
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