Mucosal Postcodes - Understanding T-Cell Trafficking in the Oral Mucosa

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

The immune system is responsible for defending the body and keeping it healthy. When the immune system does not work properly problems such as arthritis, cancer and gum diseases can occur. The body has millions of immune cells that must be able to travel to different parts of the body to mediate their effects. By reading a 'chemical map' immune cells know their location in the body. Different parts of the body have different 'chemical postcodes'. These are chemicals that tell the cell its current place in the body. How immune cells read the chemical map in the mouth is currently unknown.

This project aims to identify what the chemical postcode is for the mouth and identify how immune cells read the map in health and disease. To do this the genetic code from the mouth, and the immune cells in the mouth will be analysed. This will tell us:
1. How immune cells in a healthy mouth read the chemical map
2. How Immune cells move to the mouth in when the immune system is responding to threat
3. What the mouth's chemical post code is

The immune cells in the will be looked at in healthy mouths, and mouths that have developed an immune response. This will show how immune cells move to the mouth in health, and when the immune system in the mouth is responding to trouble.
It is not currently understood how the immune cells are instructed to read this map. We believe that saliva may play a role in this. We will look to see if the navigation equipment of immune cells changes when they contact saliva.

The project is going to take place at two sites: Glasgow Dental School and the Institute of Infection, Immunity and Inflammation. Therefore, the project will therefore benefit from world leading expertise in immune cells and in understanding the mouth. The data obtained will improve our understanding of how immune cells move to tissues in the mouth and will help identify new treatments for many oral diseases.

Technical Summary

Leukocytes must traffic precisely to the oral mucosa to mediate their protective effects, or disease-causing potential in health and disease. This proposal seeks to address the currently limited insights into the molecular mechanisms regulating homeostatic and antigen-specific immune cell migration to the oral mucosa. We hypothesise that chemokines, the main in vivo regulators of leukocyte migration, have a key role regulating the trafficking of T Cells, to the oral mucosa.

Using our expertise in chemokine biology and established techniques for analysing lymphocytes from the mouse oral mucosa, we will isolate T Cells that have travelled to specific murine oral mucosal sites. The transcriptome of the isolated cells T Cells from resting and antigen challenged tissue will be analysed using RNASeq. This will offer us in-depth and unbiased analysis of the T Cell transcriptome and identify molecules essential to T Cell trafficking in oral mucosa. Corresponding chemokine ligands in associated tissue will be analysed using PCR-array-based techniques. We will investigate candidate molecule inhibition in murine models using knockout mice and pharmacological blockers.

Expression of candidate molecules will be assessed in human oral mucosa and T Cells from this mucosa, in health and disease using PCR-array approaches.

We propose saliva plays a key role in the homing of T Cells to oral mucosal tissue. This will be investigated by culturing T Cells with saliva and assessing their expression of the candidate molecules identified. The homing ability of saliva-treated T Cells in vivo will be assessed by adoptive transfer of the in vitro treated cells.

These data will define the expression of chemokine receptors, and other molecules associated with T Cell homing to the oral cavity. Developing our understanding of oral leukocyte migration may lead to the identification of new therapeutic targets for multiple debilitating oral diseases.

Planned Impact

Introduction
Elucidating the fundamental mechanisms of leukocyte recruitment to oral mucosal tissues has a wide range of applications. T Cells are present in periodontal (gum) disease and myriad other oral pathologies (including lichen planus, oral ulceration and play a role in oral cancer angiogenesis and development). As such defining the mechanisms that regulate navigation of T Cells to oral mucosal tissue will provide valuable insights into the relatively poorly understood immune-pathophysiology of oral disease.

Industry and Commercial Sector
Improving our understanding of T Cell trafficking may highlight novel therapeutic targets. This will identify new avenues for medication development in the treatment of multiple oral diseases; benefiting those involved in drug development. In turn this may support continued economic output from these companies nationally and internationally.

Clinicians
The improved understanding of oral disease pathology will increase the knowledge base of the clinicians involved in the treatment of oral and immune mediated diseases. Currently there is a limited evidence base for the treatment and management of many oral diseases. The proposed research directly tackles this issue by highlighting the immune mechanisms that may play a role in disease development. This improved understanding will in turn lead to better treatment of oral diseases regularly encountered by clinicians and may influence evidence-based practice policy.
Economy
Many oral immune mediated diseases are chronic in nature and are associated with a significant economic burden. By improving our understanding and treatment of these diseases we will reduce the clinical time required to manage these conditions reducing the economic cost to society.

Patients
As outlined above the proposed research will improve our understanding of oral disease, identify novel therapeutic agents and reduce the economic burden of disease. These impacts combined will overall reduce the morbidity, and in some instances mortality, of a range of debilitating oral diseases. An improved understanding of disease will allow patients to better understand their condition, which would lead to an improvement in the health and well-being of these patients.

Oral and Immunology Research
The proposed research will have a profound impact on our understanding of the immune systems role in the oral cavity. To achieve this, new and existing protocols will be developed. This will lead to an improved knowledge economy and facilitates future research in immunology and oral biology.

Dental Service
Importantly it has been highlighted there are significant shortages of academics with both dentistry and oral medicine. The skills developed during my PhD will be essential for my subsequent clinical academic career in Oral Medicine. As such this will allow me to fill this void within dental academia, improving the research and teaching at the institution where I will be based.

University of Glasgow
The proposed research is collaborative in nature between The Institute of Infection, Immunity and Inflammation and Glasgow Dental School. Research of this nature is of high priority to both parties, furthering this relationship will improve ties and make future collaboration easier, leading to further academic output.

The Public
A key aspect of any research is public engagement. Disseminating new and exciting findings can be a vehicle to engaging the public with science and health care. This leads to an improved appreciation of science and what it can do for society, whilst potentially inspiring the next generation to pursue careers in STEM subjects.

Publications

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