The Lord Laboratory investigates the immune cells of patients with the inflammatory bowel diseases (IBD’s) ulcerative colitis (UC) and Crohn’s disease, and in healthy individuals with genetic risk factors for these diseases. Immune cells isolated from the blood are compared with similar cells isolated from colonoscopically biopsied or surgically resected intestine, to identify characteristics associated with dysregulated mucosal immunity. Efforts are underway to characterize such cells by flow cytometry, mRNA transcript expression, cytokine production and in vitro function, and correlate these findings with disease behavior, activity and treatment.
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 is interested in addressing this paradox in three ways: (1) The phenotypes of mucosal and circulating Tregs from IBD patients are being compared with controls in terms of their in vitro suppressive function, as well as their expression of numerous proteins associated with their differentiation and function which could identify potential defects intrinsic to the Tregs which may not be apparent by in vitro assays of their suppressive function. (2) The phenotypes of other lymphocytes (particularly FOXP3- effector CD4+ T cells) in IBD patients are being compared with those of controls to see if they are unusually resistant to the suppressive function of Tregs, and if this resistance can be attributed to unusual differentiation or expression of certain proteins. (3) The effect of intestinal antigen-presenting cells (APC) upon the inhibitory function of Tregs in vitro is being dissected, as the laboratory has found that some subsets of APC from the bowels of IBD patients can impair the inhibitory activity of Tregs.
The Lord Laboratory is also extending into IBD the efforts pioneered by BRI researchers Alice Long, PhD, and Jane Buckner, MD, to identify genetic factors influencing the signaling of immune hormones, called cytokines, in type 1 diabetes. As there are genetic risk factors for diabetes that overlap with IBD, the team is analyzing the influence of both disease and genetics upon signaling by a panel of cytokines in a variety of immune cells. This work is being done in conjunction with experiments to characterize the circulating immune cells of IBD patients and controls, so that the effect on signaling defects upon the character of the immune system can be identified within the same sample.
To support the above studies, the Lord Laboratory has been deeply invested in the founding of an IBD-specific biorepository at Benaroya Research Institute (BRI). This program has archived tissue and mucosal immune cells from the surgically resected bowels of patients with IBD and controls, and actively collects colonoscopic biopsies and blood specimens from patients with IBD through the Digestive Disease Institute at Virginia Mason. In addition to supporting the immediate studies of the Lord Laboratory at BRI, this biorepository has provided synergistic opportunities to collaborate with the greater immunology community in the Seattle area, amplifying our internal efforts to describe the immune characteristics of IBD in humans.