| Gastric cancer is the third leading cause of cancer related deaths in the world. Chronic inflammation in the gastric mucosa, caused by infection with Helicobacter pylori and/or autoimmune gastritis, is an important factor in the development of metaplasia and pre-neoplastic lesions that lead to gastric cancer. Efforts to eradicate H. pylori have emerged as a potential means of reducing the risk of gastric cancer with varying results. New strategies to reduce chronic inflammation in the gastric mucosa are needed to prevent and treat gastric cancer.;In Chapter 2, we characterize the TxA23 mouse model of autoimmune gastritis and establish this as a new model to study gastric carcinogenesis. Disease in TxA23 mice share many molecular and pathological features observed during gastric carcinogenesis in humans, providing direct evidence that autoimmune gastritis supports the development of gastric neoplasias. Like in humans, chronic gastritis in the TxA23 model is caused primarily by an autoimmune response allowing us to study the role of the immune system on gastric carcinogenesis in the absence of other factors such as chemicals or bacteria. Regulatory T cells (Tregs) are a subset of immunosuppressive CD4+ T cells critical for maintaining immune homeostasis and preventing autoimmunity. Harnessing the suppressive abilities of Tregs could lead to novel therapies for a number of diseases caused by chronic inflammation and unregulated immune cell activation. This concept has been demonstrated in animal models through the adoptive transfer of Tregs. Conventional thinking in the field of tumor immunology suggests the elimination of Tregs and/or their functions will boost anti-tumor immune responses mediated by effector T cells. However, in cancers that arise from chronic inflammation caused by autoimmunity, we hypothesize that increasing the number and/or function of Tregs may reduce causative factors and reduce the risk of cancer.;In Chapters 3 and 4, we use TxA23 mice to determine if antigen specific TGF-beta induced Tregs (iTregs) are effective at suppressing chronic inflammation and stopping progression from gastritis towards gastric cancer. After adoptive transfer, iTregs suppressed gastric pathology, maintained Foxp3 expression, and increased expression of inhibitory receptors, cytokines, and several transcription factors, associated with Treg suppressor functions.;Furthermore, we identified mechanisms used by Tregs to suppress disease, including regulating migration of T cells and suppressing key inflammatory cytokines. Collectively, we demonstrated that the adoptive transfer of antigen specific iTregs is an effective means to suppress gastritis and its progression to gastric cancer in a newly described model of gastric carcinogenesis. |
