CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS 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 thewinged–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 underwentbonemarrowtransplantationfrom the human leukocyte antigen–identical heterozygote brother was studied to investigate, in thisuniquemodel, the roleof the thymus in immunologic reconstitution. Despite an increase in CD31, CD41, and CD81 cells, CD41 CD45 RA naive lymphocytes were not regenerated. Conversely, naive CD81 cells were normal. After an initial recovery, lymphocyte proliferation to mitogens progressively declined compared with controls and genotypically identical donor cells grown in the WHN1/2 environment. Analysis of the T-cell receptor (TCR) repertoire of CD41 cells revealed that only 3 of 18 Vb families had an altered CDR3 heterogeneity length profile. Conversely, CD81 lymphocytes showed an abnormal distribution in most Vb families. These data indicate that the thymus is differentially required in thereconstitutionofCD41 and CD81 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. (Blood. 2001;97:880-885)