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.
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.
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.
Microbiology and Molecular Genetics
Daila S. Grildey
Carlos A. Casiano
James D. Kettering
John E. Lewis
George A. Nelson
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Lung Neoplasms -- radiotherapy; Whole-Body Irradiation; Remission Induction; Immune System -- radiation effects; Dose-Response Relationship; Radiation.
Loma Linda University Libraries
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.
Miller, Glen Michael, "Potential Mechanisms Explaining the Antitumor Effect of Total-Body Irradiation" (2003). Loma Linda University Electronic Theses, Dissertations & Projects. 1340.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives