ENHANCED HUMAN CD4(-CELL ENGRAFTMENT IN BETA(2)-MICROGLOBULIN-DEFICIENT NOD-SCID MICE() T)

Genetic crosses produced NOD/LtSz mice doubly homozygous for the sever e combined immunodeficiency (scid) mutation and the beta(2)m (B2m) nul l allele. Both NOD/LtSz-scid/scid and NOD/LtSz-scid/scid B2m(null) mic e lacked mature lymphocytes and serum Ig. However, homozygosity for th e B2m(null) allele also resulted in the absence of MHC class I express ion, loss of NK cell activity, accumulation of iron in the liver, and rapid clearance of human IgG1. NOD/LtSz-scid/scid B2m(null) mice suppo rted markedly elevated levels of human T cell engraftment, compared wi th NOD/LtSz-scid/scid control animals, following injection with human PBMC. The increased engraftment was associated with a major increase i n the number of human CD4(+) T cells. Following injection with 20 mill ion human PBMC, levels of human CD4(+) T cells in the peripheral blood and spleen of NOD/LtSz-scid/scid B2m(null) mice were 6- to 7-fold hig her than those in NOD/LtSz-scid/scid mice and >50-fold higher than tho se in C.B-17-scid/scid mice. The resulting normalization of CD4(+)/CD8 (+) ratios in NOD/LtSz-scid/scid B2m(null) mice is in sharp contrast t o that observed in NOD/LtSz-scid/scid mice or in C.B-17-scid/scid mice . Circulating human IgG was cleared 6-fold more rapidly in NOD/LtSz-sc id/scid B2m(null) mice than in NOD/LtSz-scid/scid mice. This rapid IgG clearance suggested a failure of the engrafted human lymphoid cells t o maintain high circulating levels of human IgG. The higher levels of human CD4(+) T cells and the normalization of the CD4:CD8 ratio that a re observed in human PBMC-engrafted NOD/LtSz-scid/scid B2m(null) mice suggest that this system may be an excellent model for studies of HIV pathogenesis.