Reconstitution of T-cell compartment after in utero stem cell transplantation: analysis of T-cell repertoire and thymic output.
OBJECTIVE
In utero transplantation of hematopoietic stem cells allows immune reconstitution of fetuses with severe combined immunodeficiency. The objective of this work was to study the quality of T-cell reconstitution following this procedure.


METHODS
We evaluated the kinetics and extent of T-cell reconstitution in five infants with severe combined immune deficiency (SCID), three with a B+ and two with a B- phenotype, who received haploidentical stem cell transplantation before birth. To this end, we measured the frequency of T-cell receptor excision circles (TREC) and the diversity of the T-cell repertoire.


RESULTS
In utero transplantation led to engraftment of donor-derived T lymphocytes which attained normal numbers in four infants, who are in good health. In the three patients with a B+ phenotype, generation of a heterogeneous T-cell repertoire was associated with development of TREC levels comparable to those of SCID patients treated by post-natal transplantation and of healthy babies. Of the two patients with a B- phenotype, one developed mixed T-cell chimerism and a substantial number of circulating T cells, associated with a variable heterogeneity of the T-cell repertoire; TREC levels were normal soon after birth, but declined thereafter. The remaining B- patient remained lymphopenic with a skewed T-cell repertoire and very low TREC levels. This patient eventually required transplantation from a matched unrelated donor at 5 years of age, but died of EBV-related lymphoproliferative disease.


CONCLUSIONS
These data indicate that in utero transplantation of fetuses with B+ SCID allows generation of newly diversified T lymphocytes and ensures long-term reconstitution of cell-mediated immunity.
Pirovano
Silvia
S
Terzo Servizio Analisi, Spedali Civili of Brescia and Department of Chemistry, University of Brescia, Italy.
Notarangelo
Luigi Daniele
LD
Malacarne
Fabio
F
Mazzolari
Evelina
E
Porta
Fulvio
F
Lanfranchi
Arnalda
A
Giliani
Silvia
S
Zucca
Sandro
S
Pecorelli
Sergio
S
Albertini
Alberto
A
Ugazio
Alberto G
AG
Imberti
Luisa
L
D000328:Adult; D005260:Female; D046128:Fetal Therapies; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007107:Immune System / Q000502:physiology; D007223:Infant; D011247:Pregnancy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012038:Regeneration; D016511:Severe Combined Immunodeficiency / Q000628:therapy; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000502:physiology
D011948:Receptors, Antigen, T-Cell