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In addition to previous evidence for a role of L3T4+ T cells in the protective anti-parental tumor immunity induced by xenogenized variant cells of a murine lymphoma (L5178Y/DTIC), we have investigated the possible participation in this effect of L5178Y tumor-specific lymphocytes of the Lyt-2+ T cell subset. Spleen cells from L5178Y/DTIC tumor-immunized mice produced high levels of IFN-gamma in vitro in response to parental antigens, and this activity was only abolished by treating the responder population with anti-Thy-1.2 antibody or a combination of anti-L3T4 and anti-Lyt-2.2 monoclonal antibodies (MAbs) plus complement. Positively selected L3T4+ and Lyt-2+ cells also produced IFN-gamma in vitro, provided accessory cells (plastic-adherent and Thy-1- Ia- splenocytes, respectively) were added to the lymphocyte-tumor cell cocultures. The production of IFN-gamma by purified L3T4+ and Lyt-2+ cells was inhibited by addition of the respective anti-class-II and anti-class-I H-2 antibody to the cultures. Administration of anti-IFN-gamma MAb in vivo significantly impaired the resistance of L5178Y/DTIC-immune mice to challenge with parental cells, as manifested by survival criteria and increased tumor-cell proliferation in the spleens of antibody-treated mice. Although anti-parental tumor protection in vivo and T-cell activation in vitro for IFN-gamma production were strictly antigen-specific, bystander tumor inhibition was observed when antigenically irrelevant cells were inoculated with the L5178Y lymphoma. These results suggest that both L3T4+ and Lyt-2+ T cells play a role in the protective anti-parental tumor immunity induced by xenogenized cells, and that their activity may involve IFN-gamma-mediated stimulation of non-specific tumoricidal mechanisms.

The ability of mouse brain to provide T-dependent antilymphoma graft responses was studied in a model in which graded numbers of tumor cells were implanted intracerebrally into recipient hosts. By using survival criteria, it was possible to demonstrate the occurrence of both primary and secondary responses against tumor-associated histocompatibility antigens in allogeneic models as well as tumor-associated transplantation antigens in histocompatible recipients. The patterns of this intracerebral graft resistance did not differ significantly from those of peripheral T-dependent immune reactivity. The findings are discussed with regard to the concept of the brain as an immunologically privileged site.

Systemic adoptive immunotherapy with specifically immune lymphocytes was successfully performed in immunodepressed mice challenged intracerebrally with L5178Y/DTIC lymphoma cells, a tumor subline rendered highly immunogenic through in vivo exposure to 5-(3,3-dimethyl-1-triazenyl)-IH-imidazole-4-carboxamide (DTIC). The systemic immunotherapy relied on the infusion of the in vitro-generated primary cytotoxic T-lymphocytes (CTL), the anti-tumor activity of which was evaluated by measuring tumor-cell proliferation in the brain in terms of radiolabel uptake and by recording survival times of recipient leukemic mice. The protection afforded by CTL appeared to be specific and was largely conditioned by dose and time of CTL administration. The levels of protection correlated well with the in vitro killing of L5178Y/DTIC tumor cells.