Physiologic human T-cell responses to OKT3 in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse model.

Abstract

Our goal was to study physiologic responses of human T lymphocytes to OKT3 in the human peripheral blood lymphocyte-severe combined immunodeficiency (hu-PBL-SCID) mouse model. SCID mice were pretreated with anti-asialo-GM1 (alpha-ASGM1) and radiation, then engrafted with human peripheral blood lymphocytes (PBLs). Seven to 14 days after engraftment, when most human T cells in the spleen of these mice are CD3+/CD4+ and CD3+/CD8+, mice were treated with OKT3 or control antibody. Mice were killed for histopathologic examination, for flow cytometric assessment of the engrafted human lymphocytes, and for analysis of human tumor necrosis factor-alpha serum levels. Intravenous injection of 5 microg of OKT3 resulted in early antigenic modulation of engrafted human T lymphocytes, with the emergence of CD3-/CD4+ and CD3-/CD8+ cells in the spleen of hu-PBL-SCID mice. There was an increase in the serum concentration of human tumor necrosis factor-alpha within 4 hr after OKT3 injection, suggesting early T-cell activation. Antigenic modulation and activation of the human lymphocytes in the spleen was followed by their depletion within 24 hr. This human T-cell response to OKT3 in hu-PBL-SCID mice is analogous to the response in humans treated with OKT3 and in BALB/c mice injected with an anti-murine CD3 monoclonal antibody. Graft-versus-host disease in the mice was abrogated by OKT3 treatment, and OKT3-treated mice lived longer than controls. Histopathologic studies showed clearance of lymphocytic infiltration in the liver and lungs of OKT3-treated mice. These findings provide further evidence of functional human immune T cells in the hu-PBL-SCID mouse. This model may have useful applications in the study of transplantation immunology.