Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.
BACKGROUND
Immune function can be restored in infants with severe combined immunodeficiency by transplantation of unfractionated bone marrow from HLA-identical donors or T-cell-depleted marrow stem cells from haploidentical donors, with whom there is a single haplotype mismatch, without the need for chemotherapy before transplantation or prophylaxis against graft-versus-host disease. The role of the thymus in this process is unknown.


METHODS
We analyzed the phenotypes of circulating T cells and the proliferative responses of peripheral-blood mononuclear cells to phytohemagglutinin in 83 patients with severe combined immunodeficiency who received allogeneic marrow transplants without T-cell ablation from related donors over an 18-year period. We also tested for the presence of episomes of T-cell antigen receptors (extrachromosomal DNA circles formed during intrathymic T-cell development) to assess thymus-dependent T-cell reconstitution.


RESULTS
Before and early after transplantation, the numbers of circulating T cells were low, with a predominance of mature CD45RO+ T cells (primarily resulting from the transplacental transfer of maternal cells); T-cell antigen-receptor episomes were undetectable in peripheral-blood mononuclear cells. In 73 of the infants, thymus-derived T cells expressing CD45RA and T-cell antigen-receptor episomes were detected within three to six weeks after transplantation. The mean (+/-SD) value for thymus-dependent T-cell antigen-receptor episomes peaked (at 7311+/-8652 per microgram of peripheral-blood mononuclear-cell DNA) 1 to 2 years after transplantation and declined to low levels (less than 100 episomes per microgram of DNA) within 14 years, as compared with a gradual decline from birth to the age of about 80 years in normal subjects.


CONCLUSIONS
The vestigial thymus in infants with severe combined immunodeficiency is functional and can produce enough T cells after bone marrow transplantation to provide normal immune function.
Patel
D D
DD
Department of Medicine, Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. patel003@mc.duke.edu
Gooding
M E
ME
Parrott
R E
RE
Curtis
K M
KM
Haynes
B F
BF
Buckley
R H
RH
D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D017493:Leukocyte Common Antigens; D018655:Lymphocyte Count; D010641:Phenotype; D010957:Plasmids / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology* / Q000502:physiology
D011948:Receptors, Antigen, T-Cell; D017493:Leukocyte Common Antigens