Prenatal T-cell reconstitution after in utero transplantation with fetal liver cells in a patient with X-linked severe combined immunodeficiency.
OBJECTIVE
Fetuses with severe combined immunodeficiency may be treated with intrauterine transplantation of fetal hematopoietic stem cells. In previous reports on intrauterine transplantation with T-cell-depleted bone marrow, repeated injections have led to partial immunoreconstitution at birth, with subnormal T-cell counts and a delayed response to mitogens.


METHODS
A male fetus with X-linked severe combined immunodeficiency because of a stop mutation in the gene encoding the common gamma chain of cytokine receptors was transplanted in week 14 of gestation with a single injection of 7 x 10(7) cryopreserved nucleated fetal liver cells (9 x 10(8) cells per estimated kilogram fetal weight) into the fetal abdomen. At 24 and 33 weeks of gestational age, fetal blood samples were taken to detect evidence of engraftment. Fetal mixed chimerism was determined using polymerase chain reaction amplification of a variable number of tandem repeats and was verified by genomic HLA class II typing and flow cytometry.


RESULTS
The course of pregnancy, delivery, and the first 18 months of life have been uncomplicated. At week 24 of gestation, donor HLA class II alleles were detected at a low level in the background of the recipient's fetal HLA genotype. The chimeric proportion of donor cells was about 10% at 24 weeks of gestation, increasing to 50% at 33 weeks of gestation. Whereas the T-cell fraction was still markedly reduced in week 24, it increased thereafter and was in the normal range from week 33 of gestation. In vitro response to T-cell mitogens was normal from birth.


CONCLUSIONS
In utero transplantation of cryopreserved fetal liver cells in week 14 of gestation with a single injection led to complete T- and NK-cell reconstitution at birth. Signs of engraftment were found already in week 24 of gestation. We consider intrauterine transplantation a valuable experimental method and a useful adjunct to postnatal transplantation and gene therapy in the treatment of severe combined immunodeficiency.
Westgren
Magnus
M
Center for Fetal Medicine, Department of Obstetrics and Gynecology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden. magnus.westgren@obgyn.hs.sll.se
Ringdén
Olle
O
Bartmann
Peter
P
Bui
The-Hung
TH
Lindton
Bim
B
Mattsson
Jonas
J
Uzunel
Mehmet
M
Zetterquist
Henrik
H
Hansmann
Manfred
M
D005260:Female; D005315:Fetal Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D005323:Fetal Monitoring; D005434:Flow Cytometry; D006680:HLA Antigens / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D022781:Hepatocytes / Q000276:immunology / Q000637:transplantation*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D006680:HLA Antigens; D011993:Recombinant Fusion Proteins