Human equivalent of the mouse Nude/SCID phenotype: long-term evaluation ofimmunologic reconstitution after bone marrow transplantation

Human Nude/SCID (severe combined immunodeficiency) is the first severe comb ined immunodeficiency caused by mutation of the winged-helix-nude (WHN)gene , which is expressed in the thymus but not in the hematopoietic lineage. Th e disease is characterized by a T-cell defect, congenital alopecia, and nai l dystrophy. A Nude/SCID patient who underwent bone marrow transplantation from the human leukocyte antigen-identical heterozyote 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, C D4(+) 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-c ell receptor (TCR) repertoire of CD4(+) cells revealed that only 3 of 18 V beta families had an altered CDRB heterogeneity length profile. Conversely, CD8(+) lymphocytes showed an abnormal distribution in most V beta families . These data indicate that the thymus is differentially required in the rec onstitution of CW4(+) and CD8(+) naive subsets and in the maintenance of th eir TCR repertoire complexity Taken together, these findings suggest that b one marrow transplantation is ineffective in the long-term cure of this for m of SCID. (C) 2001 by The American Society of Hematology.