Induction of mucosal homing virus-specific CD8(+) T lymphocytes by attenuated simian immunodeficiency virus.

Induction of virus-specific T-cell responses in mucosal as well as systemic compartments of the immune system is likely to be a critical feature of an effective AIDS vaccine. We investigated whether virus-specific CD8(+) lymphocytes induced in rhesus macaques by immunization with attenuated simian immunodeficiency virus (SIV), an approach that is highly effective in eliciting protection against mucosal challenge, express the mucosa-homing receptor alpha4beta7 and traffic to the intestinal mucosa. SIV-specific CD8(+) T cells expressing alpha4beta7 were detected in peripheral blood and intestine of macaques infected with attenuated SIV. In contrast, virus-specific T cells in blood of animals immunized cutaneously by a combined DNA-modified vaccinia virus Ankara regimen did not express alpha4beta7. These results demonstrate the selective induction of SIV-specific CD8(+) T lymphocytes expressing alpha4beta7 by a vaccine approach that replicates in mucosal tissue and suggest that induction of virus-specific lymphocytes that are able to home to mucosal sites may be an important characteristic of a successful AIDS vaccine.

Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice.

Human PBMC engraft in mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation (Hu-PBL-scid mice). Hu-PBL-NOD-scid mice generate 5- to 10-fold higher levels of human cells than do Hu-PBL-C.B-17-scid mice, and Hu-PBL-NOD-scid beta2-microglobulin-null (NOD-scid-B2mnull) mice support even higher levels of engraftment, particularly CD4+ T cells. The basis for increased engraftment of human PBMC and the functional capabilities of these cells in NOD-scid and NOD-scid-B2mnull mice are unknown. We now report that human cell proliferation in NOD-scid mice increased after in vivo depletion of NK cells. Human cell engraftment depended on CD4+ cells and required CD40-CD154 interaction, but engrafted CD4+ cells rapidly became nonresponsive to anti-CD3 Ab stimulation. Depletion of human CD8+ cells led to increased human CD4+ and CD20+ cell engraftment and increased levels of human Ig. We further document that Hu-PBL-NOD-scid mice are resistant to development of human EBV-related lymphoproliferative disorders. These disorders, however, develop rapidly following depletion of human CD8+ cells and are prevented by re-engraftment of CD8+ T cells. These data demonstrate that 1) murine NK cells regulate human cell engraftment in scid recipients; 2) human CD4+ cells are required for human CD8+ cell engraftment; and 3) once engrafted, human CD8+ cells regulate human CD4+ and CD20+ cell expansion, Ig levels, and outgrowth of EBV-related lymphoproliferative disorders. We propose that the Hu-PBL-NOD-scid model is suitable for the in vivo analysis of immunoregulatory interactions between human CD4+ and CD8+ cells.

Human peripheral blood xenografts in the SCID mouse: characterization of immunologic reconstitution.

Immune reconstitutions (hu-PBL-SCID mice) resulting from adoptive transfer of human peripheral blood mononuclear cells into 1800 C.B-17 scid-/scid-mice were characterized. Over 90% of reconstitutions were successful as evidenced by human immunoglobulin production. Variability was noted with donor, cell number, and cell type. Human cells (T lymphocytes, few B cells) could be recovered by 5 days after engraftment. High levels of soluble CD8 and interleukin-2 receptors were detected in sera of hu-PBL-SCID mice. Cells recovered from 17 mice proliferated in response to antigens to which the donor had been primed; responses to nonboosted antigen also increased in some animals. After reconstitution, lymphocytes were found in the spleen and lymph nodes without full restoration of normal architecture. The hu-PBL-SCID mouse shows promise as a model system for a variety of immunologic studies. The inherent variation in the system must be minimized for appropriate use of the model.