Research

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Overview

The Snapper laboratory is interested in the mechanisms that control immune responses and function in the gastrointestinal tract as well as host-microbial interactions that, in turn, regulate immune homeostasis in the intestine.

To this end, we have employed several basic, translational, and clinical research strategies to understand and define not only the constituents but also the mechanisms that regulate intestinal homeostasis as it pertains to gastrointestinal health and disease with a primary focus on inflammatory bowel disease (IBD) and primary immunodeficiencies. A new ambitious clinical research endeavor is the Roadmap to Cure of Early Childhood IBD Project that is the focus of the InterNational Early Onset Pediatric IBD Cohort Study (NEOPICS).

Basic Research

Intestinal Epithelial Cells

A fundamental function of the intestinal epithelium is to regulate the bidirectional flux of molecules across its barrier, and the lack of proper barrier regulation is central to human pathologic entities such as inflammatory bowel disease and enteric infection. The integrity of this barrier is determined primarily by the apical junction complex (AJC)—a multiprotein organelle comprised of the tight junction (TJ) and adherens junction (AJ), which is intimately linked to the intracellular actin cytoskeleton, and forms an occlusive seam between neighboring epithelial cells. The AJC is highly dynamic, and maintenance of this barrier requires the ability to rapidly adjust levels of junction proteins such as JAM, occludin, claudins, and ZO-1. Rapid control of junction protein composition cannot be regulated at the level of transcription alone, and junction proteins must therefore exist in preformed cytoplasmic or membrane-bound pools, ready for rapid mobilization into or out of the AJC. Despite the critical importance of the AJC as a determinant of epithelial function, relatively little is known about the fundamental mechanisms that control the transport of junction proteins to and from the AJC. Our lab is actively investigating the cellular constituents and mechanisms that function in AJC assembly and turnover.

Immune Cells and Cytokines

Over the past two decades, numerous mouse models of inflammatory bowel disease (IBD) demonstrate a critical role for balancing T cell responses to maintain intestinal immune homeostasis. In addition to T cells, recent data indicate that innate immune cells known as dendritic cells are sufficient to trigger colitis if they have functional defects even in the absence of adaptive immune T cells. Moreover, primary immune deficiencies, which can affect both the innate and adaptive immune systems, are frequently associated with intestinal inflammation. However, because of the broad distribution of immune cells affected by immunodeficiencies, the precise roles of the adaptive and innate immune cells during initiation of an inflammatory response remain unclear. Our research aims to dissect the molecular mechanisms by which innate immune cells instruct adaptive immune T cells to become regulatory T cells with anti-inflammatory functions or effector T cells that drive gut inflammation.

The regulation of cytokines (proteins secreted by immune and epithelial cells) in the intestine and lymphoid organs is critical for the overall  digestive health. The involvement of cytokines, particularly pro-inflammatory cytokines like TNF, are commonly elevated in patients with IBD and associated with disease pathogenesis. Current therapeutic strategies have focused on blocking pro-inflammatory cytokines and though effective, are not without complications and side effects.  On the other hand, IL-10 is a cytokinethat has been shown to mediate a range of anti-inflammatory activities, and numerous studies have demonstrated its importance in IBD. IL-10-mediated signaling inhibits the induction of pro-inflammatory cytokines. IL-10Rb deficient mice develop spontaneous colitis and our lab was a part of a study that reported that children harboring mutations in the IL-10R genes develop severe early onset IBD. In addition, we recently identified polymorphisms within the IL-10R genes that are associated with increased risk of early onset ulcerative colitis. We are now studying the mechanisms of how IL-10R signaling in different immune cells is involved in maintaining mucosal homeostasis and how defective signaling can lead to perturbations in mucosal homeostasis. Understanding these mechanisms will provide new insights and therapeutic approaches for treating patients with IBD. 

Translational Research

Humanized Mice as a Translational Research Tool

One of the goals of basic science research is to take our discoveries at the bench and transition these findings into clinical therapeutic applications. For patients with mucosal immunopatholgies resulting from primary immunodeficiencies or inflammatory bowel disease (IBD), increased activation of particular T cell subsets and/or dysfunctional regulatory cells is associated with intestinal inflammation and disease pathogenesis. Several studies in mice show that regulatory T cells are critical to maintain intestinal immune homeostasis, and defects in the number and/or function of these regulatory T cells is sufficient to promote intestinal inflammation. However, a critical barrier to understanding the function of human regulatory T cells in the intestinal mucosa is the inability to study these cells within the appropriate context in vivo. Since our lab is interested in mechanisms regulating immune homeostasis in the intestinal mucosa, we developed novel mouse strains that permit us to study the role of human immune cells in mice. This novel approach is laying a foundation for these models to become important pre-clinical tools that will allow development and testing of novel therapeutic strategies that promote human immune homeostasis.

 

Clinical Research

Roadmap to the Cure of Early Childhood IBD

Infantile and very early onset (VEO) inflammatory bowel disease is a severe and debilitating form of intestinal inflammation that has shown the most dramatic increase in incidence over the past decade and now makes up over 25% of all Pediatric IBD. Infantile and VEO-IBD patients often suffer from a severe disease that does not respond to traditional therapies or surgery and unfortunately sometimes results in death. In order to understand and treat these young children we have established an international consortium made up of clinicians and scientists from North America, Europe, Australia, South America, Israel and the Middle East.  Our singular mission is the ambitious goal of both understanding the basis for these diseases as well to develop effective therapies.

The Roadmap to the Cure of Early Childhood IBD project is led by co-PIs Scott Snapper from the United States, Aleixo Muise from Canada, and Christoph Klein from Germany (please see attached bios). All co-PIs have been committed to fully understanding the genetic and functional aspects of this form of IBD and their recent work has led to discovery of novel genes resulting in alternate therapies for defined subgroups of infantile and VEO-IBD. The collaboration brings together the InterNational Early Onset Pediatric IBD Cohort Study (NEOPICS) in North America and the Care for Rare Study in Europe. Furthermore, sites in Israel, Australia, Brazil, Chile, and the Middle East have joined our collaborative study. Together these consortia already have access to DNA from over 550 very early onset IBD patients many with stool, RNA, and biopsy samples. The inclusion of more US and European pediatric centers to the NEOPICS consortium will greatly increase the number of patient in a very short timeframe. This valuable resource will allow for rapid discovery of genetic determinants of infantile and VEO-IBD.

Pediatric Inflammatory Bowel Disease Biospecimen Repository

With the etiology of inflammatory bowel disease (IBD) still largely unknown, the pediatric inflammatory bowel disease biospecimen repository will create a resource for investigators to test research hypotheses in the areas of disease pathogenesis, diagnostics, and prognosis. Our repository will collect samples from patients with Crohn’s disease (CD) and ulcerative colitis (UC) as well as patients with debilitating, immune-mediated chronic bowel inflammation, including indeterminate colitis (IC) and primary immunodeficiencies that manifest with chronic bowel inflammation (eg. common variable immune deficiency, Wiskott-Aldrich syndrome). The development of an institutional IBD data registry will augment the value of the biospecimen repository as all samples will be annotated and linked to important clinical information. This will allow for easy integration of clinical and biological data.

GEM Project (A Multidisciplinary Human Study on the Genetic, Environmental and Microbial Interactions that Cause IBD)

The greatest identifiable risk for development of Crohn's disease is having a first-degree family member affected by Inflammatory Bowel Disease (IBD). The cause of IBD is unknown but speculated to involve complex gene-environment interactions where susceptible individuals mount abnormal host responses to environmental factors such as resident gut microorganisms. The GEM Project will attempt to determine if specific gene-environment triggers can be identified. For this prospective study, unaffected siblings of Crohn's disease patients will be recruited and information on environmental exposures will be collected prospectively while simultaneously obtaining and storing biological samples on all subjects with the cohort. These subjects will be followed for up to 6 years. When a "sufficient" number of subjects have developed Crohn's disease, a nested case-control sampling of this cohort will allow for a focused examination of the changes in the microbial flora, intestinal permeability, immune response to bacterial antigen (Ag) and immune regulation, in relation to expressed IBD susceptibility genes. This will allow us to determine which pathogenic events may have contributed to disease prior to disease development.

CCFA Microbiome Study

Complex interactions between host genetics, environment and immunity shape the intestinal microbiome. Abnormalities in any of these factors can provoke intestinal inflammation characteristic of IBD and many immunodeficiency syndromes. The precise nature of these interactions remains poorly understood. Genetic factors associated with Inflammatory Bowel Disease (IBD) explain a modest fraction of disease risk. While alterations of the intestinal microbiome have been described in IBD, no individual species or group of bacteria has been consistently associated with either Crohn’s disease (CD) or ulcerative colitis (UC). Likewise, it is not yet known what role microbial biomolecular activity may play in these diseases. Using novel computational approaches of 16S rDNA and whole genome sequencing, as well as meta- transcriptomics, metabolomics, and pathway analyses, we propose to define the relationship between host genetics and the intestinal microbiome. In particular, we have the capacity to study and identify functional elements of the microbiome that influence human subjects spanning the clinical spectrum from pre- symptomatic at risk individuals to those with established IBD as well as to those with immunodeficiences associated with intestinal inflammation. We have assembled a multidisciplinary team with recognized expertise and experience in these fields and will leverage existing resources to collect the necessary cohorts.

PROTECT

This multicenter open-label study is designed to evaluate the safety and efficacy of standardized initial therapy using either mesalamine, or corticosteroids then mesalamine for the treatment of children and adolescents newly diagnosed with ulcerative colitis.

The study will investigate the hypothesis that response to the initial 4 weeks of therapy as well as specific clinical, genetic, and immune parameters determined during the initial course of therapy will predict severe disease as reflected by need for escalation of medical therapy or surgery.

Oral Anti-CD3 for the Treatment of Active Ulcerative Colitis

Ulcerative colitis (UC) is a chronic disease of unknown etiology characterized by infiltration of inflammatory cells into the intestinal tract. Anti-CD3 monoclonal antibody (MAb) is an approved drug for intravenous use in the treatment of solid-organ transplantation and phase I/II trials have demonstrated possible efficacy for the treatment of UC. However, intravenous dosing has been limited by significant toxicities. Data from animal models suggest that anti-CD3 administered via the oral route is effective at treating a variety of autoimmune diseases. No side effects were observed in a recent phase I study of healthy subjects receiving oral anti-CD3 antibody.

 

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