Iheagwara, Uzoma
(2013)
Exposure to Abnormal Self Antigens During Non-Malignant Inflammatory Events Provides Immunological Defense Against Tumors.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cancer immunosurveillance is the body’s sentinel mechanism of recognizing and eliminating malignancy. Specifically, the immune system can mount a response against cancer through the recognition of tumor associated antigens (TAA). While studying two TAAs, MUC1 and cyclin B1, our group discovered T cell and antibody responses specific for these abnormal molecules not only in cancer patients but also in healthy individuals with no cancer history. While seeking to explain why TAA specific responses exist in healthy people, our group and others’ epidemiologic studies revealed that individuals who had a history of febrile pathogenic infections had a lower risk of cancer development. These results led us to hypothesize that non-malignant events such as influenza infection, elicit abnormal expression of multiple self-antigens on infected cells and specific immune memory against those antigens. Abnormal expression of the same antigens on tumor cells triggers specific immune responses and provides adaptive immune memory to participate in tumor surveillance. Rather than classifying these abnormal molecules common to virus infected and malignant cells as TAAs, they should be recognized as disease associated antigens (DAA). I first tested this hypothesis in MUC1Tg mice and found that, influenza infection induces abnormal MUC1 expression in the lung, MUC1 specific CD8+ T cells, and that influenza experienced mice control MUC1+ tumor growth. I next addressed if this infection model could lead to the identification of other DAA. I modified the mouse model by using C57BL/6 mice, using two influenza virus strains as the stronger pathogenic insult to the lung and using a lung tumor Lewis Lung Carcinoma (3LL) as the tumor challenge. Through the use of 2D-Difference Gel Electrophoresis to resolve and identify tumor proteins detected deferentially by pre- and post-infection mouse sera, I selected from over 120 proteins five specific molecules (DAAs) for further iv
study: GAPDH, Histone H4, HSP90, Malate Dehydrogenase 2 and Annexin A2. Western blot analysis confirmed their overexpression in two mouse tumor cell lines and in flu-infected lungs compared to healthy lungs. Additionally I confirmed that antibodies and CD8+ T cell specific responses were generated against these 5 DAAs following flu infection. Lastly, animals vaccinated with peptide derived from these candidate DAA demonstrated a prolonged delay in tumor growth. Better understanding of early life events that prepare the immune system to protect individuals against known and unknown pathogens as well as future malignancies will help direct vaccines towards strengthening life-long immunosurveillance. Importantly, these findings support the use of vaccines based on DAAs/TAAs for cancer prevention.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Iheagwara, Uzoma | uki1@pitt.edu | UKI1 | |
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| ETD Committee: |
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| Date: |
6 December 2013 |
| Date Type: |
Publication |
| Defense Date: |
26 November 2013 |
| Approval Date: |
6 December 2013 |
| Submission Date: |
6 December 2013 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
120 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Flu, tumor antigen, DAA, Influenza, TAA |
| Date Deposited: |
06 Dec 2013 17:40 |
| Last Modified: |
15 Nov 2016 14:16 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20238 |
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