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Dissertation
Age-related decrease in murine natural killer cell activity after interferon-[alpha]/[beta] stimulation
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Jun 1999
DOI:
https://doi.org/10.17918/00008883
Abstract
Natural Killer (NK) cells, important in viral infections and anti-tumor activity, show reduced cytotoxicity in aged mice. A mechanism for the age-related decline has not been clearly established. IFN-[alpha]/[beta], a cytokine that is involved in the natural defense against viral infections can also have anti-tumor activity in part by activating NK cell cytotoxicity in vitro and in vivo against NK sensitive targets. We therefore assessed changes in NK cytotoxicity in spleen and peripheral blood cells after IFN-[alpha]/[beta] stimulation, in adult (6 months) and aged (22-26 months) C57Bl/6 (B6), Balb/c and C57Bl/6xBalb/c-F1 (CB6-F1) hybrid mice. Aged B6 and Balb/c mice had a significantly reduced IFN-[alpha]/[beta]-stimulated NK cytotoxicity compared to adult mice. The CB6-F1 hybrid mice however, showed similar NK cytotoxicity after IFN-[alpha]/[beta] induction in adult and aged mice, suggesting the possibility of genetic complementation of possible defects in the parental strains. We showed that the decreased induction of NK activity by IFN-[alpha]/[beta] did not appear to be the result of suppressive activity of adherent cells or T cells. The reduced cytotoxicity aged mice was also not due to altered number of NK cells, since the percentage of NK cells (NK1.1+) of splenic and peripheral blood lymphocytes was similar in adult and aged B6 mice. Flow cytometric analysis revealed that aged mice had a higher expression of the IFN-[alpha]/[beta] receptor1, but showed similar levels of IFN-[alpha]/[beta] binding than adult mice. An increased amount of IFN-[alpha]/[beta] or a longer period of treatment with IFN-[alpha]/[beta] did not elevate NK cytotoxicity in aged mice. A higher expression of the apoptosis receptor Fas and increased target-induced apoptosis in aged compared to adult mice, suggested that a greater number of NK cells in aged mice were dying upon IFN-[alpha]/[beta] activation and target interaction. Co-stimulation with phorbol ester (PMA), significantly increased the percentage of NK cells producing IFN-[gamma] and also increased activation markers CD69 and CD25 expression similarly in adult and aged mice. NK cytotoxicity however, was significantly reduced in aged mice, suggesting a dissociation between the increase in activation markers and the reduced NK cytotoxicity after IFN-[alpha]/[beta] in aged mice. Finally we observed that a subset of NK cells, NK1.1+CD8+, was significantly increased in aged B6 mice and the percentage of NK1.1+CD8+ cells was inversely related to IFN-[alpha]/[beta] induced cytotoxicity. These results indicate that the decreased activation of NK activity in aged B6 mice is reflected in altered IFN-[alpha]/[beta] receptor expression, cytokine production and apoptosis in aged mice. These innate changes in the NK cells in addition to the increased percentage of NK1.1+CD8+ cells in aged mice, may be responsible for the reduced inducibility of NK cytotoxicity after IFN-[alpha]/[beta] stimulation.
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Details
- Title
- Age-related decrease in murine natural killer cell activity after interferon-[alpha]/[beta] stimulation
- Creators
- Paul Artur Plett
- Contributors
- Donna Murasko (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xv, 169 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888887704721