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Correlation of suppressed natural killer cell activity with altered host resistance models in B6C3F1 mice
S D Wilson1, J A McCay, L F Butterworth
1Milestone Biomedical Associates, Frederick, Maryland 21701, USA.
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 > or =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 > or =80% decrease in spontaneous NK activity in mice, challenge with > or =1 x 10(3) B16F10 melanoma cells resulted in an increase in tumor burden based on the number of lung nodules. However, following challenge with 1 x 10(5) melanoma cells, a significant increase in tumor burden in mice was not observed until spontaneous NK activity had been decreased by > or =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.
Insights
Anti-asialo GM1 (AAGM1) antibody effectively suppresses natural killer (NK) cell activity in mice for up to three weeks. This suppression impacts host resistance to melanoma, with altered resistance depending on both NK cell reduction and tumor challenge size.
Area of Science:
- Immunology
- Toxicology
- Cancer Research
Background:
- Assessing xenobiotic impact on immune system components is crucial for risk analysis.
- Determining the link between chemically induced immune perturbation and altered host resistance is necessary.
- Natural killer (NK) cells are key innate immune cells with cytotoxic functions against pathogens and tumors.
Purpose of the Study:
- To investigate the effect of anti-asialo GM1 (AAGM1) antibody on NK cell activity.
- To evaluate the impact of NK cell suppression on host resistance to B16F10 melanoma.
- To determine the relationship between the magnitude of NK cell reduction and host resistance.
Main Methods:
- Intravenous administration of varying dilutions of AAGM1 antibody to B6C3F1 mice.
- Measurement of spontaneous NK cell activity.
- Assessment of host resistance through challenge with B16F10 melanoma cells and evaluation of tumor burden.
Main Results:
- AAGM1 antibody administration decreased spontaneous NK activity by 20% to over 80%, with suppression lasting up to 3 weeks.
- NK cell suppression did not affect other immune cell functions tested (plaque assay, MLR, CTL, RES clearance, S. pneumoniae resistance).
- Significant increase in B16F10 melanoma tumor burden was observed with >80% NK cell reduction and a low tumor cell challenge (≥1 x 10^3).
- A 50-60% reduction in NK activity led to increased tumor burden only with a higher tumor cell challenge (1 x 10^5).
Conclusions:
- AAGM1 antibody is an effective agent for suppressing NK cell activity in mice.
- Altered host resistance to tumors is dependent on both the degree of NK cell suppression and the magnitude of the tumor challenge.
- This study provides insights into the role of NK cells in host defense against cancer and the complexities of chemical immunotoxicity.
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