HIV Infection , and Adoptive Transfer for Engraftment of Human Hematolymphoid Immunodeficient and Radioresistant Model Mice : An nullRag 1 NOD /

Development of a small animal model for the in vivo study of human immunity and infectious disease remains an important goal, particularly for investigations of HIV vaccine development. NOD/Lt mice homozygous for the severe combined immunodeficiency (Prkdc scid) mutation readily support engraftment with high levels of human hematolymphoid cells. However, NOD/LtSz-scid mice are highly radiosensitive, have short life spans, and a small number develop functional lymphocytes with age. To overcome these limitations, we have backcrossed the null allele of the recombination-activating gene (Rag1) for 10 generations onto the NOD/LtSz strain background. Mice deficient in RAG1 activity are unable to initiate V(D)J recombination in Ig and TCR genes and lack functional T and B lymphocytes. NOD/LtSz-Rag1 null mice have an increased mean life span compared with NOD/LtSz-scid mice due to a later onset of lymphoma development, are radioresistant, and lack serum Ig throughout life. NOD/LtSz-Rag1 null mice were devoid of mature T or B cells. Cytotoxic assays demonstrated low NK cell activity. NOD/LtSz-Rag1 null mice supported high levels of engraftment with human lymphoid cells and human hemopoietic stem cells. The engrafted human T cells were readily infected with HIV. Finally, NOD/LtSz-Rag1 null recipients of adoptively transferred spleen cells from diabetic NOD/Lt؉/؉ mice rapidly developed diabetes. These data demonstrate the advantages of NOD/LtSz-Rag1 null mice as a radiation and lymphoma-resistant model for long-term analyses of engrafted human hematolymphoid cells or diabetogenic NOD lymphoid cells. T he establishment of a functional human immune system reconstituting a small animal model is a goal of many workers investigating human immunity and human-specific infectious agents such as HIV-1 (1–3). Since the first reports of low levels of engraftment of human hematolymphoid cells in C.B-17 mice homozygous for the severe combined immunodefi-ciency (Prkdc scid) mutation (hereafter abbreviated as scid) (3–5), we have focused on optimizing this model by manipulating the host strain background to increase levels of human cell engraft-ment. We have provided evidence that NOD/LtSz-scid mice support levels of human hematolymphoid engraftment that are ϳ5-fold higher than those observed in C.B-17-scid mice (1, 6 –10). Recently, we have demonstrated that NOD/LtSz-scid mice ho-mozygous for the ␤2-microglobulin null allele (B2m null) support even higher levels of human cell engraftment than do NOD/LtSz-scid mice (11). The data support the hypothesis that the host strain background strongly modulates the level of achievable human cell engraftment in this model system. We have continued to focus on the NOD/Lt genetic background …