Transplantation resistance of drug‐treated hybrid or allogeneic mice against murine lymphomas. I. Immunopharmacology studies

Sequential treatment of mice with non‐lethal doses of 5(3,3′‐dimethyl‐I‐triazeno)‐imidazole‐4‐carboxamide (DTIC) and cyclophosphamide (Cy) was found to produce long‐term inhibition of endogenous cell proliferation in the spleen and profound impairment of classical allograft responses, similar to that detectable in lethally irradiated mice. Studies were carried out with drug‐treated (i.e. treated with DTIC + Cy) conventional or nude mice inoculated with lymphoma cells homozygous for the H‐2b or H‐2d haplotype. Transplantation resistance in various tumor‐host combinations was studied in terms of survival times after tumor challenge or lymphoma cell proliferation in spleen and liver, measured by the uptake of DNA precursor 125I‐labelled 5‐iodo‐2′‐deoxyuridine ([125I]dUrd). The results of in vivo transplantation immunity tests or in vitro tests of generation of cytotoxic lymphocytes confirmed that classical T‐dependent allograft responses were abrogated by drug treatment of H‐2‐incompatible hosts. However, localized resistance against lymphoma graft, mainly at spleen level, was found in drug‐treated hybrid mice, or conventional and “nude” allogeneic recipients, as judged by [125I]dUrd uptake inhibition. Resistance presumably regulated, at least in part by the Hh (hemopoietic histocompatibility) system, was abrogated by pretreatment with carrageenan, an antimacrophage agent. In addition, treatment with DTIC + Cy did not abrogate NK activity of mice when the in vitro cytotoxicity test was conducted 5h after Cy administration, i.e. at the time used for tumor challenge in vivo. It was concluded that selected immunological functions (i.e., antilymphoma natural resistance insensitive to DTIC + Cy, called drug‐resistant inhibition of tumors, DRIT) possibly of non‐T origin, similar to those detectable in lethally‐irradiated mice, can be retained by hosts subjected to high doses of certain anti‐tumor agents.