The Lord Laboratory investigates the immune cells of patients with the inflammatory bowel diseases (IBD’s) ulcerative colitis (UC) and Crohn’s disease. To support this research, the Lord Laboratory has been deeply invested in an IBD biorepository at Benaroya Research Institute (BRI). This program has archived blood and intestinal tissue from hundreds of participating patients with or without IBD through the Digestive Disease Institute at Virginia Mason. Immune cells isolated from these specimens are characterized by flow cytometry, mRNA transcript expression, cytokine production and in vitro function. Correlating these findings with disease behavior, activity and treatment then provides novel insights into how IBD happens, and what we can do about it.
T cells in IBD
Animal models, genetics and the drugs we use to treat IBD all suggest that T cells play a very important role in both Crohn’s disease and ulcerative colitis. The Lord laboratory has been investigating several of the less common types of T cells that may play a particularly important role in IBD or it’s prevention.
Of particular interest are FOXP3+ regulatory T cells (Tregs), as these cells play a pivotal role in controlling mucosal inflammation. Indeed, humans and system models without Tregs develop severe intestinal inflammation, resembling IBD.
However, patients with IBD actually have a paradoxical excess of FOXP3+ Tregs in their intestinal mucosa, particularly in the setting of active disease. Therefore, the Lord Laboratory has been addressing this paradox by comparing the intestinal Tregs of IBD patients with those of healthy controls, to determine why the plethora of Tregs present in IBD nonetheless fail to control inflammation.
More recently the Lord lab has also extended its analyses to mucosa-associated invariant T (MAIT) cells, about which surprisingly little is known in IBD. These cells recognize vitamin precursors made by the normal bacteria of the gut, and hence may play a critical role in the interface between immunology, nutrition and the gut microbiome.
Taking a more reductionist approach to the microbiome, the Lord lab has identified and cloned T cells which recognize one specific part (a peptide from the OmpC protein) of the normal gut bacteria called E. coli. While such cells were found to exist in people with and without IBD, the ones from patients with Crohn’s disease lack certain immune hormones, called cytokines, which are important for regulating the immune system.
Biomarker Discovery and IBD Treatments
As the diversity of treatment options available to IBD patients has grown in recent years, there has been a growing need to be able to predict which drugs will work best in which patients. By characterizing the immune cells from IBD patients before they start a given therapy, the Lord lab has been working to find what is different in such cells between the patients who go on to respond well to that therapy and those who do not. Discovering such predictive “biomarkers” is essential for physicians to tailor therapy appropriately for each patient. Additionally, by seeing how the immune system changes in people who respond to a medication, the Lord lab is learning just how these drugs work to treat IBD, and from that can determine just how IBD happens in the first place. Finally, by characterizing what is different about the immune cells from patients who do not respond to therapies, the Lord lab hopes to discover immune mechanisms that cause the inflammation of IBD, but are not currently targeted by existing drugs, and thus may reveal entirely new pathways to target.