Project 4, headed by Dr. Theresa Pizarro, will focus on epithelial-immune cell interactions, specifically the interplay between the intestinal epithelium, DCs and T cells. The central hypothesis is that intestinal DCs prematurely exposed to luminal antigens as a direct consequence of an inherent defect in intestinal epithelial barrier function leads to aberrant innate DC activation that drives dysregulated adaptive immunoregulatory processes, resulting in uncontrolled chronic gut inflammation similar to that observed in CD.
Specific Aim 1 will characterize epithelial-DC interactions leading to activation of the intestinal lamina propria (LP) DC population. DCs will be purified from the LP and mesenteric lymph nodes (MLNs) of SAMP, SAMP-ChrX*B6, as well as control AKR and 86 mice. Epithelial-DC interactions will be investigated by a variety of techniques, including cytokine and chemokine measurement, FACS and in vitro cell culture analysis and static confocal and dynamic 2-photon microscopy. Finally, the impact of the bacterial flora on epithelial-DC interactions will be evaluated in germ-free (GF), compared to specific pathogen-free (SPF) SAMP mice.
In Aim 2, we will determine how inherent epithelial barrier dysfunction results in loss of intestinal resident DC anergy/tolerance and consequently drives dysregulated T regulatory cell (Treg) function. The ability of DCs from the SAMP, SAMP-ChrX*B6, and controls to polarize Teff/Treg cell populations will be assessed by multiple techniques, both in vitro and in vivo to precisely define DC/Treg interaction in this model.
Aim 3 will evaluate the precise genetic contribution of ChrX-linked genes to the development of chronic ileitis in the SAMP strain. B6-ChrX*SAMP will be generated and fine gene mapping will be performed to identify and potentially confirm candidate disease susceptibility genes on ChrX (i.e., claudin-2, TLR cluster, FoxP3) previously shown to be dysregulated in SAMP mice. The overall goal of this project is to further elucidate the mechanism(s) of chronic intestinal inflammation characteristic of CD, and identify potential, early disease pathways that can lead to targeted therapeutic strategies to treat patients suffering from this devastating disease.
CD affects more than 500,000 individuals in the US and incurs significant costs to society. Understanding the precise mechanisms and immune defects that cause the disease will allow us to develop better therapies and begin to develop a cure for this devastating disease.
|Chirieleison, Steven M; Marsh, Rebecca A; Kumar, Prathna et al. (2017) Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease. J Biol Chem 292:9666-9679|
|Menghini, Paola; Di Martino, Luca; Lopetuso, Loris R et al. (2017) A novel model of colitis-associated cancer in SAMP1/YitFc mice with Crohn's disease-like ileitis. PLoS One 12:e0174121|
|Do, Jeong-Su; Kim, Sohee; Keslar, Karen et al. (2017) ?? T Cells Coexpressing Gut Homing ?4?7 and ?E Integrins Define a Novel Subset Promoting Intestinal Inflammation. J Immunol 198:908-915|
|Cominelli, Fabio; Arseneau, Kristen O; Rodriguez-Palacios, Alexander et al. (2017) Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn's Disease-Like Ileitis: What is the Right Model? Cell Mol Gastroenterol Hepatol 4:19-32|
|Rathkey, Joseph K; Benson, Bryan L; Chirieleison, Steven M et al. (2017) Live-cell visualization of gasdermin D-driven pyroptotic cell death. J Biol Chem 292:14649-14658|
|Corridoni, D; Rodriguez-Palacios, A; Di Stefano, G et al. (2017) Genetic deletion of the bacterial sensor NOD2 improves murine Crohn's disease-like ileitis independent of functional dysbiosis. Mucosal Immunol 10:971-982|
|Ley, Klaus; Rivera-Nieves, Jesus; Sandborn, William J et al. (2016) Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 15:173-83|
|Grivennikov, Sergei I; Cominelli, Fabio (2016) Colitis-Associated and Sporadic Colon Cancers: Different Diseases, Different Mutations? Gastroenterology 150:808-10|
|Goodman, W A; Omenetti, S; Date, D et al. (2016) KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation. Mucosal Immunol 9:1250-62|
|Basson, Abigail; Trotter, Ashley; Rodriguez-Palacios, Alex et al. (2016) Mucosal Interactions between Genetics, Diet, and Microbiome in Inflammatory Bowel Disease. Front Immunol 7:290|
Showing the most recent 10 out of 76 publications