GENERATION OF PRIMARY ANTIGEN-SPECIFIC HUMAN CYTOTOXIC T-LYMPHOCYTES IN HUMAN MOUSE RADIATION CHIMERA/

Severe combined immunodeficient (SCID) mice are increasingly used as h osts for the adoptive transfer of human lymphocytes. Human antibody re sponses can be obtained in these xenogeneic chimeras, but information about the functionality of the human T cells in SCID mice is limited a nd controversial. Studies using human peripheral blood lymphocytes (PB L) injected intraperitoneally (IF) into SCID mice (hu-PBL-SCID mice) h ave shown that human T cells from these chimeras are anergic and have a defective signaling via the T-cell receptor. In addition, their anti genic repertoire is limited to xenoreactive clones. In the present stu dy, we tested the functionality of human T cells in a recently describ ed chimeric model. In this system, BALB/c mice are conditioned by irra diation and then transplanted with SCID bone marrow, followed by IP in jection of human PBL, our experiments demonstrated that human T cells, recovered from these hu-PBL-BALB mice within 1 month posttransplant, proliferated and expressed activation markers upon stimulation with an ti-CD3 monoclonal antibody, A vigorous antiallogeneic human cytotoxic T-lymphocyte (CTL) response could be generated in these mice by immuni zing them with irradiated allogeneic cells, Moreover, anti-human immun odeficiency virus type 1 (HIV-1) Nef-specific human CTLs could be gene rated in vivo from naive lymphocytes by immunization of mouse-human ch imeras with a recombinant vaccinia-nef virus, This model may be used t o evaluate potential immunomodulatory drugs or cytokines, and could pr ovide a relevant model for testing HIV vaccines, for production of ant iviral T-cell clones for adoptive therapy, and for studying human T-ce ll responses in vivo, (C) 1996 by The American Society of Hematology.