Early ReportIn-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDX1)
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
References (22)
- et al.
IL-2 Receptor gamma Chain Mutation Results in XSCID in Humans
Cell
(1993) - et al.
Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep
Blood
(1993) - et al.
Adult bone marrow–derived pluripotent hematopoietic stem cells are engraftable when transferred in utero into moderately anemic fetal recipients
Blood
(1995) - et al.
In Utero Transfer of adult bone marrow cells into recipients with severe combined immunodeficiency disorder yields lymphoid progeny with T and B cell functional capabilities
Blood
(1995) - et al.
High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown WAS
Science
(1995) - et al.
Diagnosis and classification of severe combined immunodeficiency disease
Birth Defects
(1983) - et al.
Screening for mutations causing X-linked severe combined immunodeficiency in the IL-2Rg chain gene by SSCP analysis
Hum Genet
(1995) - et al.
Diagnostic antenatal des deficits immunitaires hereditaires graves
Arch Fr Pediatr
(1985) - et al.
Preemptive therapy for genetic disease
Nature Med
(1996) - et al.
Analysis of hematological and immunological parameters in normal fetal blood at 20 weeks of gestational age
Dev Physiopath and Clin
(1993)