CONVERSION OF NORMAL RATS INTO SCID-LIKE ANIMALS BY MEANS OF BONE-MARROW TRANSPLANTATION FROM SCID DONORS ALLOWS ENGRAFTMENT OF HUMAN PERIPHERAL-BLOOD MONONUCLEAR-CELLS

We have recently shown that lethally irradiated normal strains of mice , radioprotected with SCID bone marrow, can be engrafted with human pe ripheral blood mononuclear cells (PBMC), We now demonstrate that letha lly irradiated Lewis rats can also be radioprotected with a transplant of SCID bone marrow cells, administered 1 day after total body irradi ation. Split chimerism was found in PBMC, 30 days after transplantatio n, with predominance of SCID donor-type cells. The average percentages of CD4 and CD8 T cells, of mouse or rat origin, were <1%. This chimer ism status could be maintained for over 3 months, When human PBMC (300 -1000x10(6) cells) were transplanted intraperitoneally 1 day after the administration of SCID bone marrow, prompt engraftment of human CD4 a nd human CD8 T cells, as well as human CD20 B cells, was found in the peritoneum and in internal organs (such as liver, lung, spleen, thymus , and lymph nodes), T cell activation was high: about 50% of the cells expressed HLA-DR and almost all expressed CD45RO. High titers of huma n Ig (>1 mg/ml) were initially found after 2 weeks; these levels were similar to those found in the irradiated mouse model and in the SCID m odel. Likewise, marked human antitetanus response, predominantly of th e IgG type, was recorded 2 weeks after the immunization, reaching maxi mal levels at 4 weeks, The triple-chimeric SCID-like rats, which accep t as much as 1000x10(6) human PBMC, can potentially be used to elicit both antibody responses and T cell responses against specific antigens , with the advantages of a larger animal.