Gastric carcinoma is the second most common cause of cancer related deaths worldwide. Helicobacter pylori (H. pylori) has been identified as a major causative agent in gastric cancer. H. pylori infection is common worldwide, acquired during childhood and unless treated, infection can persist for years causing a precancerous cascade of gastric epithelial damage leading to gastric carcinoma. H. pylori pathogenesis is essentially an imbalance in immune homeostasis;T-helper and T- regulatory lymphocytes have been implicated in H. pylori pathogenesis and links between Th1, Th2, Th17, regulatory T cells and other T-cell populations remained to be defined. Studying the role of these lymphocytes may be critical for understanding the mechanism of H. pylori persistence, the failure of the host immune response to H. pylori infection, and the development of H. pylori-associated diseases including gastric cancer. The long term objective of this project is to characterize the T-helper and T-regulatory cell populations and understand their role in H. pylori-induced gastric epithelial damage in a p27-deficient mouse model. The first specific aim is to characterize the T-helper and T-regulatory cell populations in chronic H. pylori infection in a p27-deficient model by examining T-helper, T-regulatory cell populations, their functional properties and their effects on the gastric epithelium during chronic H. pylori infection.
The second aim i s to elucidate the role of CD4+CD25+Foxp3+ regulatory T-lymphocytes during chronic H. pylori infection in a p27-deficient mouse model via depletion of regulatory T-cells. After depletion, T-helper populations and their effects on gastric epithelial damage during chronic H. pylori infection will be evaluated. For both aims T-helper and regulatory cell populations will be enumerated via flow cytometric analysis, immunohistochemistry and realtime polymerase chain reaction. Gastric epithelial damage will be determined via apoptotic assays and histological analysis.
For aim two specifically, CD4+CD25+Foxp3+ depletion will be performed using anti- CD25 monoclonal antibody (PC61). This project will give researchers and clinicians a better understanding on how the development of a skewed T-helper response controlled by regulatory T-cells manipulated by chronic H. pylori infection may lead to development of cancer. Elucidating the mechanism of H. pylori-induced immunopathogenesis and understanding the role T lymphocyte populations play in H. pylori persistence is critical in the development of new methods of H. pylori eradication and cancer prevention.
| Ruiz, Victoria E; Sachdev, Monisha; Zhang, Songhua et al. (2012) Isolating, immunophenotyping and ex vivo stimulation of CD4+ and CD8+ gastric lymphocytes during murine Helicobacter pylori infection. J Immunol Methods 384:157-63 |
| Kim, Sung Soo; Ruiz, Victoria E; Carroll, Jaqueline D et al. (2011) Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma. Cancer Lett 305:228-38 |
