Potential Mechanisms Explaining the Antitumor Effect of Total-Body Irradiation

<p>While numerous reports have documented that radiation exposure increases the risk for malignancy and suppresses immune mechanisms, increasing evidence has suggested that low-dose total-body irradiation (TBI) may alter leukocyte composition and function leading to heightened immune responsiveness and long-term remission of certain cancers. Having observed that moderate-dose TBI produces an antitumor effect in the Lewis lung carcinoma (EEC) model, the major goal of this study was to determine whether changes in tumor growth could be correlated with radiation-induced alterations of immune system parameters. The governing hypothesis was that selective immune augmentation, i.e. upregulation of specific leukocyte subsets, is primarily responsible for the reduction in lung carcinoma progression that follows administration of moderate-dose TBI.</p> <p>Alterations in cytokine secretion, lymphocyte cytotoxicity, and immune cell population densities were investigated at sequential time points when delivery of TBI (0.46 to 3.0 Gray of γ-rays) preceded EEC implantation in the C57BL/6 mouse model. Tumor volumes and mouse weights were measured throughout each protocol; and immunohistochemical analyses were performed on tumors excised from control and test mice to evaluate leukocyte infiltration. In later studies, mice were injected with depleting antibodies to eliminate NK populations, in order to determine the contribution of the NK subset to the antitumor effect of TBI.</p> <p>Collectively, the data demonstrated for the first time that a selective radiation-induced reconstitution of T suppressors, NK, and NKT populations as well as cytokine profile are correlated to a protumoricidal immune environment following TBI. Changes in the relative percentages and activation status of immune cell compartments, that accompany TBI, functioned to slow tumor progression. Further, experimentation substantiated that asialo GM1+ and NK1.1+ cells operated in tumor surveillance in the LLC tumor model and were involved in mediating the antitumor effect of TBI. The findings also demonstrated that radiation exposure can activate NK cells, inducing increased population densities and cytotoxicity, thereby leading to tumor suppression. The finding, that moderate-dose TBI can enhance tumor surveillance of NK cells, warrants further study and evaluation.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Year

2003

Author dc:creator

• Miller, Glen Michael

Contributors dc:contributor

• Daila S. Grildey
• Carlos A. Casiano
• James D. Kettering
• John E. Lewis
• George A. Nelson

• Immune System Diseases
• Microbiology
• Molecular Genetics
• Lung Neoplasms -- radiotherapy; Whole-Body Irradiation; Remission Induction; Immune System -- radiation effects; Dose-Response Relationship; Radiation.

Statement dc:rights

• This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/1340

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-2110