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.