Inflammation and Inflammatory Bowel Disease
My laboratory studies the regulation of inflammation as it relates to the intestine and other mucosal surfaces. Helminths are worm-like animals that can live in the intestine or elsewhere in the body. Using murine models of disease, we study how helminths influence the host's mucosal immune response to limit inflammation. Helminths induce regulatory immune cells and regulatory pathways in the host. Active investigation is pursuing the mechanisms that lead to development of these regulatory circuits and how these circuits function. The research has particular importance for understanding the cause of inflammatory bowel disease and other immunological diseases of people. These studies my result in novel and innovative new treatment strategies for control of these conditions.
It is believed that inflammatory bowel disease results from a dysregulated mucosal immune system. There appears to have been a rapid rise in the frequency of inflammatory bowel disease over the last 50 years. The major hypothesis of one of our projects is that modern day lack of exposure to intestinal helminths is an important factor contributing to the growth of IBD. It is believed that childhood exposure to helminths modulates the mucosal immune system, which affords this protection.
Figure 1. A model of the way helminths affect the T cell response is illustrated in the diagram.
To test this hypothesis, we have established several animal models of IBD in which intestinal worms provide protection. We use transgenic mice, and molecular and immunological techniques to unravel the immune mechanisms of protection.
Figure 2. Effect of H. polygyrus colonization on established colitis. (A-C) Typical colonic inflammation 2 weeks after finishing piroxicam treatment in IL-10-/- mice that did not receive H. polygyrus. (D-F) Typical colon histology in mice colonized with H. polygyrus for 2 weeks after piroxicam treatment. A-F Hematoxylin and eosin staining, ×40. Bar graph shows colitis inflammatory scores. Inflammation was scored on a 0-4 scale by pathologists blinded to the treatment group. Data are means ±SE from 11 animals studied in two separate experiments.
Neuropeptides and Mucosal Inflammation
Another project in the laboratory studies neuropeptides and how they function to control inflammation at mucosal surfaces. In particular, we are investigating the role of substance P (SP) and its receptor in immune regulation. We showed that SP is a Th1-type cytokine that functions through a T cell neurokinin 1 receptor (NK-1R) to drive Th1 responses. SP and NK-1R are critical for normal immune responses in the liver and intestines as shown in animal models of intestinal infection. Humans develop an immunologic disease associated with chronic, destructive intestinal inflammation (IBD). Th1 inflammation drives human IBD (particularly Crohn's). Human and murine intestinal LPMC express NK-1R. NK-1R display is up regulated in human IBD particularly on lamina propria CD4+ T cells. The major hypothesis of this study is that NK-1R, which is the main receptor for SP, is an inducible and regulated mucosal T cell receptor that helps drive the aberrant intestinal inflammation of IBD. To test this hypothesis, we study animal models of human inflammatory bowel disease to explore the importance of T cell NK-1R in mucosal inflammation and to study mechanisms of T cell NK-1R regulation.
Figure 3. The figure depicts our working model of Substance P function.