Correlation of Suppressed Natural Killer Cell Activity with Altered Host Resistance Models in B6C3F1 Mice

Abstract

A number of methods have been developed to assess the impact of a xenobiotic on the various components of the immune system. For risk analysis, it is necessary to determine what degree of chemically induced immune perturbation translates into altered host resistance. Natural killer (NK) cells play a pivotal role in the innate immune system with the ability to lyse cells infected with intracellular pathogens and certain tumors without previous exposure to the antigen. Spontaneous NK activity in B6C3F1 mice could be incrementally and consistently decreased by 20 to ≥80% by the intravenous administration of a range of dilutions of anti-asialo GM1 (AAGM1) antibody. The decrease in spontaneous NK activity following a single iv administration of AAGM1 antibody persisted for up to approximately 3 weeks when the initial suppression (e.g., 24 h after AAGM1 antibody injection) was almost 100%. Treatment with AAGM1, however, did not appear to perturb the function of other immune cells, based on results of the plaque assay, the mixed lymphocyte response, the cytotoxic T lymphocyte assay, the reticuloendothelial system clearance of sRBC assay, and the Streptococcus pneumoniae host resistance assay. Following a ≥80% decrease in spontaneous NK activity in mice, challenge with ≥1 × 103 B16F10 melanoma cells resulted in an increase in tumor burden based on the number of lung nodules. However, following challenge with 1 × 105 melanoma cells, a significant increase in tumor burden in mice was not observed until spontaneous NK activity had been decreased by ≥50–60%. Altered host resistance is a function not only of the magnitude of the decrease in NK activity but also of the magnitude of the challenge to the host.