The success of TNF blockade for the treatment of Crohn's disease (CD) has lead to the systematic study of other biological therapies. Unfortunately, the usefulness of these newer therapies (e.g. IL-10, IL-11 blockade) has been limited. Therefore, alternative biological therapies that target other pathways of chronic intestinal inflammation must be evaluated in CD. We propose that due to redundancies in the lymphocyte adhesion cascade, simultaneous blockade of two or more gut-homing adhesion molecules and/or chemokines (i.e. L-selectin, beta7integrin, MAdCAM-1 and CCR9) will be required. Therefore, our central hypothesis is that interference with lymphocyte trafficking by targeting specific combinations of adhesion molecules/chemokines will result in amelioration of chronic ileitis in the TNFdeltaARE murine model of CD. To address this hypothesis we propose the following specific aims: 1. To identify redundancies of the lymphocyte adhesion cascade under conditions of chronic small intestinal inflammation. Using immunohistochemistry, PCR, flow cytometry and intravital microscopy we will dissect the pathways of lymphocyte trafficking in chronic ileitis and identify the molecules that support lymphocyte adhesion and migration. 2. To assess the role of gut-homing adhesion molecule/chemokines on the development of chronic ileitis. We will backcross TNFdeltaARE mice and TNFdeltaARE/beta7-/- mice to mice deficient for L-selectin and CCR9. 3. To evaluate the effectiveness of combinatorial blockade of adhesion molecules/chemokines for the treatment of established chronic ileitis. For this translational aim, we will use combinations of specific function-blocking monoclonal antibodies that may improve the effectiveness of current anti-alpha4- or alpha4beta7- integrin blockade strategies (i.e. Natalizumab, MLN02), already in clinical trials. This proposal is designed to provide the principal investigator with extensive experience in a variety of laboratory techniques, as listed on the specific aims. The strengths of 2 mentors that specialize in mucosal immunology (FC) and adhesion molecules (KFL), as well as the availability of all equipment, reagents and mouse strains required for the experiments is unique to our institution. These experiences will be complemented by a rigorous program of laboratory and classroom instruction. Given the similarities between human CD and the TNF-induced chronic ileitis in our mouse model, the proposed studies could also provide important leads for novel biological targets to treat this devastating disease.
| Wermers, Joshua D; McNamee, Eoin N; Wurbel, Marc-Andre et al. (2011) The chemokine receptor CCR9 is required for the T-cell-mediated regulation of chronic ileitis in mice. Gastroenterology 140:1526-35.e3 |
| Collins, Colm B; McNamee, Eoin N; Wermers, Joshua D et al. (2010) Chemokine decoy receptor D6 in inflammatory bowel disease (IBD) and IBD-associated colon cancer. Gut 59:151-2 |
| McNamee, Eoin N; Wermers, Joshua D; Masterson, Joanne C et al. (2010) Novel model of TH2-polarized chronic ileitis: the SAMP1 mouse. Inflamm Bowel Dis 16:743-52 |
| Collins, Colm B; Ho, Johnson; Wilson, Theodore E et al. (2008) CD44 deficiency attenuates chronic murine ileitis. Gastroenterology 135:1993-2002 |
| Ho, Johnson; Kurtz, Courtney C; Naganuma, Makoto et al. (2008) A CD8+/CD103high T cell subset regulates TNF-mediated chronic murine ileitis. J Immunol 180:2573-80 |
| Rivera-Nieves, Jesus; Burcin, Tracy L; Olson, Timothy S et al. (2006) Critical role of endothelial P-selectin glycoprotein ligand 1 in chronic murine ileitis. J Exp Med 203:907-17 |
| Rivera-Nieves, Jesus; Ho, Johnson; Bamias, Giorgos et al. (2006) Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis. Gastroenterology 131:1518-29 |
| Rivera-Nieves, Jesus; Olson, Timothy; Bamias, Giorgos et al. (2005) L-selectin, alpha 4 beta 1, and alpha 4 beta 7 integrins participate in CD4+ T cell recruitment to chronically inflamed small intestine. J Immunol 174:2343-52 |
