Although extensive work has been done in the area of leukocyte trafficking in normal and inflamed tissues such as the skin and small intestine, the colon is relatively unexplored. We hypothesize that selective combinations of adhesion molecule expression identifies subsets of T cells that preferentially home to the colon. We propose that T cells enter the colon via specific homing molecules. Following local anitgen [sic] primiming [sic] the T cells exit to draining lymph nodes and later re-enter colon lamina propria as effector T cells using additional specific trafficking molecules/mechanisms. This hypothesis is supported by findings that subsets of lymphocytes, via their expression of unique combination of adhesion molecules, manifest differential tissue localization for e.g. in the small intestine and the skin. Based on these hypotheses, the specific aims of my proposal are:
Aim 1. Generate an in vivo model to study colon-specific targeting of antigen-reactive T cells. Here we will use recently described model of inducing antigen specific T cell within the colon using cholera toxin and ovalbumin immunizations. We will use flow cytometry and immunohistochemistry to determine the kinetics of trafficking receptor expression during T cell activation and induce effector antigen specific T cells capable of efficiently entering the colon lamina propria with secondary colon immunizations.
Aim 2. Determine mechanisms of antigen specific T cell trafficking to the colon. Using similar techniques above [sic] we will determine trafficking molecule expression during T cell activation and during entry to or exit from the colon. We will then determine whether the trafficking molecules identfied [sic] mediate recruitment of colon T cells. The role of the trafficking molecules will be studied using adhesion blocking antibodies and where available chemokine receptor deletion transgenic mice. Identification of unique trafficking molecules or specialized combination of trafficking receptors on colon lymphocytes will improve our understaining [sic] of immune cell trafficking to the colon and offer potentially new therapeutic targets for inflammatory bowel disease (IBD).
The relevance of this project to autoimmune diseases affecting the intestine, such as inflammatory bowel disease (IBD) is tremendous. My mentor and his group have previously identified and characterized the physiologic roles of adhesion molecules targeting leukocyte traffic such as the (4(7 integrin;[sic] which have led to key application and clinical trials of a recombinant monoclonal antibody against (4-integrin (natalizumab), in the treatment of IBD such as Crohn's disease (21). Findings from my studies could lead to better understanding of preferential immune cell trafficking to the colon and potentially offer new insights into IBD therapeutic targets and understanding the pathogenesis of IBD.
|Ocón, Borja; Pan, Junliang; Dinh, Theresa Thu et al. (2017) A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15. Front Immunol 8:1111|
|Habtezion, Aida; Nguyen, Linh P; Hadeiba, Husein et al. (2016) Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology 150:340-54|
|Zeng, R; Oderup, C; Yuan, R et al. (2013) Retinoic acid regulates the development of a gut-homing precursor for intestinal dendritic cells. Mucosal Immunol 6:847-56|