Human equivalent of the mouse Nude/SCID phenotype: long-term evaluation of immunologic reconstitution after bone marrow transplantation.
Human Nude/SCID (severe combined immunodeficiency) is the first severe combined immunodeficiency caused by mutation of the winged-helix-nude (WHN) gene, which is expressed in the thymus but not in the hematopoietic lineage. The disease is characterized by a T-cell defect, congenital alopecia, and nail dystrophy. A Nude/SCID patient who underwent bone marrow transplantation from the human leukocyte antigen-identical heterozygote brother was studied to investigate, in this unique model, the role of the thymus in immunologic reconstitution. Despite an increase in CD3(+), CD4(+), and CD8(+) cells, CD4(+) CD45 RA naive lymphocytes were not regenerated. Conversely, naive CD8(+) cells were normal. After an initial recovery, lymphocyte proliferation to mitogens progressively declined compared with controls and genotypically identical donor cells grown in the WHN(+/-) environment. Analysis of the T-cell receptor (TCR) repertoire of CD4(+) cells revealed that only 3 of 18 Vbeta families had an altered CDR3 heterogeneity length profile. Conversely, CD8(+) lymphocytes showed an abnormal distribution in most Vbeta families. These data indicate that the thymus is differentially required in the reconstitution of CD4(+) and CD8(+) naive subsets and in the maintenance of their TCR repertoire complexity. Taken together, these findings suggest that bone marrow transplantation is ineffective in the long-term cure of this form of SCID.
Pignata
C
C
Department of Pediatrics and Cellular and Molecular Biology and Pathology, "Federico II" University, Naples, Italy. pignata@unina.it
Gaetaniello
L
L
Masci
A M
AM
Frank
J
J
Christiano
A
A
Matrecano
E
E
Racioppi
L
L
D000505:Alopecia / Q000151:congenital / Q000235:genetics*; D000818:Animals; D000917:Antibody Formation; D003241:Consanguinity; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D016130:Immunophenotyping; D007231:Infant, Newborn; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009928:Organ Specificity; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D013950:Thymus Gland / Q000002:abnormalities; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014184:Transplantation, Homologous
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C090140:Whn protein