The CD4 T cell response to Helicobacter pylori and its role in the development of gastric adenocarcinoma.
Lead Research Organisation:
University of Nottingham
Department Name: Nottingham Digestive Diseases Centre
Abstract
Half the world‘s population is infected by the germ Helicobacter pylori (Hp), the main cause of stomach cancer. The human immune response influences the outcome of Hp infection. This project will help establish why some people with Hp develop cancer, whereas most do not.
T-helper cells are a particular type of white blood cell critical in co-ordinating the immune response. Hp infection causes both inflammatory and anti-inflammatory (regulatory T-cell) responses. Regulatory T-cells are increased in Hp-infected patients and in a number of cancers including stomach cancer.
A new subtype of inflammatory T-helper cells, named Th17 has recently been described and is currently attracting much interest. My preliminary data demonstrates the presence of these T-cells in the Hp-infected stomach.
I hypothesize that Th17-mediated inflammation contributes to the immune response to Hp, is not controlled adequately by the anti-inflammatory regulatory T-cells and is important in the development of cancer.
Different types of T-helper cells present in Hp-infected patients with no cancer, pre-cancerous changes and with cancer will be characterized and the interactions between the different T-cell groups will be studied. The project will also give insight into how factors produced by these cells contribute to inflammation and cancer development.
T-helper cells are a particular type of white blood cell critical in co-ordinating the immune response. Hp infection causes both inflammatory and anti-inflammatory (regulatory T-cell) responses. Regulatory T-cells are increased in Hp-infected patients and in a number of cancers including stomach cancer.
A new subtype of inflammatory T-helper cells, named Th17 has recently been described and is currently attracting much interest. My preliminary data demonstrates the presence of these T-cells in the Hp-infected stomach.
I hypothesize that Th17-mediated inflammation contributes to the immune response to Hp, is not controlled adequately by the anti-inflammatory regulatory T-cells and is important in the development of cancer.
Different types of T-helper cells present in Hp-infected patients with no cancer, pre-cancerous changes and with cancer will be characterized and the interactions between the different T-cell groups will be studied. The project will also give insight into how factors produced by these cells contribute to inflammation and cancer development.
Technical Summary
Helicobacter pylori (Hp) colonizes the stomachs of half the world‘s population and causes gastric adenocarcinoma, the second commonest cause of cancer death worldwide. This project will investigate the cellular immune response to Hp infection, and how this influences inflammation and carcinogenesis.
Hp infection is known to cause a T-helper (Th)1 inflammatory response and an anti-inflammatory T-regulatory cell (T-reg) response. T-reg numbers are increased in Hp-infected patients, and in a number of cancers including gastric adenocarcinoma. A novel interleukin-17 (IL-17)-secreting T-helper subset (Th17) has recently been described. IL-17 is increased in the Hp-infected stomach and has an important role in recruiting neutrophils, which are prominent in the Hp-infected stomach. My preliminary data demonstates CD4+IL-17 (putative Th17) cells in the Hp-infected gastric mucosa. IL-17 is angiogenic and a growth factor for human mesenchymal stem cells, suggesting it may also have pro-oncogenic effects. Th17 cells are increased in a number of human cancers.
Aims
I aim to address the hypotheses
1. Th17 cells contribute to the cellular immune response to Hp.
2. Unlike Th1 proinflammatory cells, Th17 cells are not subject to T-reg control.
3. Th17 cells have pro-carcinogenic effects and, like T-regs, are increased in Hp+ patients with pre-cancerous changes and gastric adenocarcinoma.
Objectives
1. To quantify and characterize Th1, Th17 and T-reg cells in the human gastric mucosa and peripheral blood of Hp- patients and Hp+ patients with (i) gastritis only (ii) pre-cancerous changes (iii) gastric adenocarcinoma.
2. To determine the effect of T-regs on Th1 and Th17 responses to Hp.
3. To determine the effects of Th1, Th17 and T-reg cytokines on expression of pro-inflammatory and carcinogenesis-associated genes in vitro and correlate with in vivo data.
Methodology/Design
Gastric and peripheral blood lymphocytes from from Hp+ and Hp- donors attending the Nottingham University Hospitals for upper GI endoscopy or partial gastric resection surgery will be characterized using flow cytometry. Co-culture experiments will be used to determine the effect of T-regs on Th1 and Th17 responses to Hp. Real-time-PCR and western blotting will be used to study the expression of pro-inflammatory and pro-carcinogenic genes both in ex-vivo gastric tissue samples and in human gastric epithelial cell line in vitro.
Scientific and medical opportunities
This will provide insight into the role of Th17 cells in bacterial infection and carcinogenesis and the interactions of this novel T-cell population with T-regs as well as helping to elucidate why a minority of Hp-infected patients develop gastric adenocarcinoma.
Hp infection is known to cause a T-helper (Th)1 inflammatory response and an anti-inflammatory T-regulatory cell (T-reg) response. T-reg numbers are increased in Hp-infected patients, and in a number of cancers including gastric adenocarcinoma. A novel interleukin-17 (IL-17)-secreting T-helper subset (Th17) has recently been described. IL-17 is increased in the Hp-infected stomach and has an important role in recruiting neutrophils, which are prominent in the Hp-infected stomach. My preliminary data demonstates CD4+IL-17 (putative Th17) cells in the Hp-infected gastric mucosa. IL-17 is angiogenic and a growth factor for human mesenchymal stem cells, suggesting it may also have pro-oncogenic effects. Th17 cells are increased in a number of human cancers.
Aims
I aim to address the hypotheses
1. Th17 cells contribute to the cellular immune response to Hp.
2. Unlike Th1 proinflammatory cells, Th17 cells are not subject to T-reg control.
3. Th17 cells have pro-carcinogenic effects and, like T-regs, are increased in Hp+ patients with pre-cancerous changes and gastric adenocarcinoma.
Objectives
1. To quantify and characterize Th1, Th17 and T-reg cells in the human gastric mucosa and peripheral blood of Hp- patients and Hp+ patients with (i) gastritis only (ii) pre-cancerous changes (iii) gastric adenocarcinoma.
2. To determine the effect of T-regs on Th1 and Th17 responses to Hp.
3. To determine the effects of Th1, Th17 and T-reg cytokines on expression of pro-inflammatory and carcinogenesis-associated genes in vitro and correlate with in vivo data.
Methodology/Design
Gastric and peripheral blood lymphocytes from from Hp+ and Hp- donors attending the Nottingham University Hospitals for upper GI endoscopy or partial gastric resection surgery will be characterized using flow cytometry. Co-culture experiments will be used to determine the effect of T-regs on Th1 and Th17 responses to Hp. Real-time-PCR and western blotting will be used to study the expression of pro-inflammatory and pro-carcinogenic genes both in ex-vivo gastric tissue samples and in human gastric epithelial cell line in vitro.
Scientific and medical opportunities
This will provide insight into the role of Th17 cells in bacterial infection and carcinogenesis and the interactions of this novel T-cell population with T-regs as well as helping to elucidate why a minority of Hp-infected patients develop gastric adenocarcinoma.