Unconventional T-Cell Immunity in the Initiation of Inflammatory Bowel Disease
Abstract
FY20 PRMRP Topic Area: Inflammatory Bowel Disease Inflammatory bowel disease (IBD) encompasses Crohn’s disease and ulcerative colitis. IBD commonly presents from childhood into early adulthood. In 2017, there were estimated to be 6–8 million cases of IBD globally, with an estimated 3 million sufferers in North America. Common symptoms include diarrhea, abdominal pain, and rectal bleeding. Extra-intestinal manifestations may also extend to the joints, eyes, and skin. Unfortunately, IBD diagnoses are on the rise, there is no available cure, and treatment options are limited. Current treatments include lifelong immunosuppressants or anti-inflammatory medications. These treatments leave patients at an increased risk from common viral, bacterial, or fungal infections. In addition, almost a third of patients do not respond to treatment. There is an urgent and currently unmet need to develop a better understanding of the biological mysteries at the commencement of IBD. This knowledge will help stimulate new therapies to improve the long-term impact of this condition for military personnel and the wider community. A major hurdle in developing new IBD therapeutics has been a lack of understanding of the factors that contribute to the commencement of the condition. One area we lack clarity on is the immune systems dysregulation in IBD. The gastrointestinal tract contains billions of microorganisms living in harmony with the immune system. These microbes are separated from immune cells by a barrier, called the intestinal epithelium. The immune cells that patrol and protect this barrier include specialized cells that express a T cell receptor (TCR), and termed, T cells. These T cells are able to respond and react to characteristic molecules the microbes produce, known as antigens. It is thought that an inadvertent TCR-mediated response may trigger a chain of events that result in gastrointestinal inflammation and intestinal damage, at the root of IBD. In this project, we will study a poorly understood group of T cells that express a particular TCR called a gamma delta TCR. These gamma delta T cells are major population that patrol the intestinal epithelium. We believe the changes in gamma delta T cells is directed by their TCRs. We have access to gut samples from children and young adults, in the earliest stages of IBD. We will explore these concepts using world leading and innovative techniques to look at the gamma delta TCR interactions in extraordinary detail. We will uncover how these TCRs change in healthy patients compared to IBD and understand the details of the surface interactions that drive these responses. Together, our studies will allow us to understand how the gut contents drive the gamma delta T cell response in IBD. Together, these studies will provide detailed information on an often overlooked immune network in IBD. This work will firmly establish our ability to design new strategies to manipulate this immune response. We believe our research and the new therapies it will lead to will help to limit the impact and damage of IBD. In the future, this innovative research will help to improve the quality of life for Service members, their families, and the community at large.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110175
Entities
People
- Martin S Davey
Organizations
- Monash University
- United States Army