OHSU

Zhang Lab Current Projects

IL-17 Project

Recent Th17/IL-17 research has prompted the formulation of a new concept that is having a profound impact on the elucidation of T cell-mediated diseases including uveitis and inflammatory bowel disease. Traditionally, CD4+ T cells have been separated into two different subsets namely Th1 and Th2. A new subset of T helper cells called Th17 has now been described. Th17 cells elicit IL-17-dependent inflammation. Our laboratory has recently established a novel antigen-specific and CD4+ cell-dependent uveitis model, which enables us to further investigate the roles of Th17 in uveitis.  In addition, we routinely perform intravital microscopy.  This technology greatly enhances our ability to study ocular inflammation and leukocyte infiltration.

Intravital microscopy of ocular leukocyte infiltration after antigen challenge








Intravital microscopy of ocular leukocyte infiltration after antigen challenge


Intraocular trafficking of T lymphocytes (red) and neutrophils (green)

Intraocular trafficking of T lymphocytes (red) and neutrophils (green)

OX40 Project

Both generation and recruitment of sufficient autoimmune T cells are essential steps to stage a full-fledged immune response.  Th17 cells are a unique subset of CD4+ T lymphocytes implicated in host defense and many inflammatory diseases.  However, the regulatory mechanism of Th17 proliferation and migration has not been defined completely.  Recent studies have shown that the ligation of several co-stimulatory receptor-ligand pairs contributes to the development and migration of the Th17 T cell subset.  OX40, a co-stimulatory molecule expressed on the surface of CD4+ T cells during their activation process, is known to promote the proliferation and differentiation of some T cell subsets.  We aim to investigate whether OX40 plays a role in Th17 cell activation, expansion, and migration. 

Our view of T cell activation process through the lens of M.C. Escher

Our view of T cell activation process through the lens of M.C. Escher

CD40 Project

Eosinophilic esophagitis is an emerging disease characterized by marked eosinophil infiltration into the esophagus.  It is strongly associated with allergy and Th2 response. However, the molecular mechanism of activation of Th2 cells implicated in eosinophilic esophagitis is not yet fully defined.  Currently, we are investigating whether CD40 (CD154), a co-stimulatory molecule expression by antigen presenting cells, contributes to the development of eosinophilic esophagitis.  We hope that our study in the animal model and human patient will advance our understanding of eosinophilic esophagitis and facilitate development of future therapeutic strategies.

Cross section of mouse esophagus

Cross section of mouse esophagus

Histology of eosinophilic esophagitis

Histology of eosinophilic esophagitis

Past

Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel disease (IBD), are gastrointestinal disorders characterized by chronic and relapsing inflammation. IBD affects millions of peoples in the world. Dr. Crohn and his colleagues were the first to describe the disease as "regional ileitis" in 1930's. Since then, tremendous progress has been made to understand and treat this devastating disease.

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Salicylates                                               Macroscopic IBD

Present

Recent research in genetics, immunology, cell biology, and pharmacology has greatly impacted and shaped the management of IBD in modern day. Anti-TNF-alpha therapy is one successful illustration of translating basic research to clinical application. Nevertheless, curing IBD is still an arduous path ahead of us.

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TNF-alpha                                              Endoscopic IBD

Future

The future success of conquering IBD relies on continuation of research from bench side to bedside. Like many research groups, the Zhang laboratory is aimed to understand the functional effect of gene mutations associated with IBD and to define critical mediators implicated in the pathogenesis of gastrointestinal inflammation. Our ultimate goal is to develop novel therapeutic strategy with more anti-inflammatory efficacy and less suppressive effects on host defense.

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Novel genes and cytokines                  Capsule endoscopy of IBD

Research Profile

L-17 Project

Recent IL-23/IL-17 research has prompted the formulation of a new concept that is having a profound impact on the elucidation of T cell-mediated diseases including IBD. Traditionally, CD4+ T cells have been separated into two different subsets namely Th1 and Th2. A new IL-23-driven subset of T helper cells called ThIL-17 has now been described. The data suggest that IL-23 plays an important role in the differentiation of autoreactive pathogenic T cells. IL-23-driven CD4+ T cells are highly pathogenic and elicit IL-17-dependent inflammation in several autoimmune diseases as well as IBD. Recently Mannon and his colleagues have demonstrated that infusion of monoclonal antibody against IL-12p40 is efficacious in treating Crohn's disease. However, the IL-12p40 subunit is shared by IL-23. Thus, neutralization of IL-23 and subsequent suppression of IL-17 could be responsible for the therapeutic effect of this novel reagent. In fact, IL-23p19, the other subunit of IL-23, and IL-17 are elevated in intestinal tissue of patients with IBD. Consistent with these clinical observations, we previously showed that IL-17 expression is augmented in experimental colitis models. In light of these progresses, we will further investigate the roles and relationships of co-stimulatory molecules such as CD40, IL-23 and ThIL-17 cells in IBD and IBD-related uveitis. This study will greatly enhance the understanding of IBD pathogenesis and facilitate development of future therapeutic strategies.

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Schematic of ThIL-17 cell differentiation and regulation

NOD2 Project

Nucleotide-binding oligomerization domain 2 (NOD2) is an intriguing molecule of host defense and bacteria recognition. The discovery of NOD2 protein has highlighted the importance of the innate immunity in many physiological as well as pathological processes. NOD2 is expressed in myeloid cells. It has the ability to respond to specific bacterial cell wall component called muramyl dipeptide (MDP) and plays a role in the response to invasive bacteria. NOD2 mutations are recently associated with a common inflammatory condition, Crohn's disease and a rare, autosomal-dominant disease called Blau syndrome. Both diseases are characterized by granulomatous inflammation. Furthermore, Crohn's disease-associated NOD2 mutation appears to influence the outcome of stem cell transplantation/graft versus host disease.

Despite recent progress in the field, it is perplexing that NOD2 mutant cells from Crohn's patients display an immune response paradoxical to the clinical manifestation. Many questions remain to be answered with regard to the physiological and pathological roles of NOD2. How do the mutations alter NOD2-mediated signal transduction, leading to an aberrant cellular response? Additionally although the Blau mutation is well documented in the literature, virtually no published studies have addressed the effect of the gene defect on cell function, leading to Blau syndrome. Furthermore, many independent studies found that Crohn's disease-associated NOD2 mutations reduced inflammatory response of monocytes to bacterial stimulation. This finding is paradoxical to clinical observation that these patients have enhanced inflammation. This disparity highlights the need of the further research for this evolving and important topic.

Blau syndrome is a rare disease and serves an ideal model for studying NOD2. We have a unique advantage to access mononuclear cells from Blau syndrome patients. Thus, we will characterize the effect of the Blau syndrome-associated NOD2 defect to better understand the mechanism of NOD2-mediated diseases, and develop therapeutic strategy.

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Contact Us

Zili Zhang, MD, PhD
Associate Professor of Pediatrics
Department of Pediatrics
Oregon Health & Science University

Mail code: CDRCP
707 SW Gaines Street
Portland, OR 97239
Fax: 503-418-1377
E-mail: zhangzi@ohsu.edu