EMV30(NULL) NOD-SCID MICE - AN IMPROVED HOST FOR ADOPTIVE TRANSFER OFAUTOIMMUNE DIABETES AND GROWTH OF HUMAN LYMPHOHEMATOPOIETIC CELLS

When used as hosts in passive transfer experiments, a stock of NOD/Lt mice congenic for the severe combined immunodeficiency (scid) mutation have provided great insight to the contributions of various T-cell po pulations in the pathogenesis of autoimmune insulin-dependent diabetes mellitus (IDDM). Moreover, NOD-scid mice support higher levels of hum an lymphohematopoietic cell growth than the C.B-17-scid strain in whic h the mutation originated. However, the ability to perform long-term l ymphohematopoietic repopulation studies in the NOD-scid stock has been limited by the fact that most of these mice develop lethal thymic lym phomas beginning at 20 weeks of age, These thymic lymphomas are charac terized by activation and subsequent genomic reintegrations of Emv30, an endogenous murine ecotropic retrovirus unique to the NOD genome. To test the role of this endogenous retrovirus in thymomagenesis, we pro duced a stock of Emv30(nuli) NOD-scid mice by congenic replacement of the proximal end of chromosome 11 with genetic material derived from t he closely related NOR/Lt strain, Thymic lymphomas still initiate in E mv30(null) NOD-scid females, but their rate of progression is signific antly retarded since the frequency of tumors weighing between 170 and 910 mg at 25 weeks of age was reduced to 20.8% vs, 76.2% in Emu30(+) s egregants, The thymic lymphomas that did develop in Emv30(null) NOD-sc id mice were not characterized by a compensatory increase in mink cell focus-forming proviral integrations, which initiate thymomagenesis in other susceptible mouse strains. Significantly, the ability of standa rd NOD T-cells to transfer IDDM to the Emv30(null) NOD-scid stock was not impaired, Similarly, the elimination of Emv30 did not abrogate the enhanced ability of NOD-scid mice to support the growth of human peri pheral blood leukocytes, These findings coupled with the slowed progre ssion of thymic lymphomas indicate that Emv30(null) NOD-scid mice are an improved, but not yet optimal, recipient for long-term lymphohemato poietic reconstitution studies that assess the mechanisms of autoimmun e IDDM development in both mice and humans.