MULTIPLE DEFECTS IN INNATE AND ADAPTIVE IMMUNOLOGICAL FUNCTION IN NODLTSZ-SCID MICE/

The scid mutation was backcrossed ten generations onto the NOD/Lt stra in background, resulting in an immunodeficient stock (NOD/LtSz-scid/sc id) with multiple defects in adaptive as well as nonadaptive immunolog ic function. NOD/LtSz-scid/scid mice lack functional lymphoid cells an d show little or no serum Ig with age. Although NOD/Lt-+/+ mice develo p T cell-mediated autoimmune, insulin-dependent diabetes mellitus, NOD /LtSz-scid/scid mice are both insulitis- and diabetes-free throughout life. However, because of a high incidence of thymic lymphomas, the me an lifespan of this congenic stock is only 8.5 mo under specific patho gen-free conditions. After i.v. injection of human CEM T-lymphoblastoi d cells, splenic engraftment of these cells was fourfold greater in NO D/LtSz-scid/scid mice than in C.B17/Sz-scid/scid mice. Although C.B-17 Sz-scid/scid mice exhibit robust NK cell activity, this activity is ma rkedly reduced in both NOD/Lt-+/+ and NOD/LtSz-scid/scid mice. Presenc e of a functionally less mature macrophage population in NOD/LtSz-scid /scid vs C.B-1 7Sz-scid/scid mice is indicated by persistence in the f ormer of the NOD/Lt strain-specific defect in LPS-stimulated IL-1 secr etion by marrow-derived macrophages. Although C.B-17Sz-scid/scid and C 57BL/6Sz-scid/scid mice have elevated serum hemolytic complement activ ity compared with their respective +/+ controls, both NOD/LtSz-+/+ and NOD/ LtSz-scid/scid mice lack this activity. Age-dependent increases in serum Ig levels (>1 mu g/ml) were observed in only 2 of 30 NOD/LtSz -scid/scid mice vs 21 of 29 C.B-17/Sz-scid/scid animals. The multiple defects in innate and adaptive immunity unique to the NOD/LtSz-scid/sc id mouse provide an excellent in vivo environment for reconstitution w ith human hematopoietic cells.