Allergy and Immunology

Faculty Research

The Rothenberg laboratory is focused on elucidating the mechanisms of allergic responses especially in mucosal tissues such as the lung and the gastrointestinal tract. The goal of the research is to identify novel pharmaceutical targets for the treatment of patients with eosinophilic diseases including eosinophilic gastrointestinal disorders, hypereosinophilic syndromes, asthma and food allergies. The laboratory has identified and biologically characterized several critical pathways that regulate allergic responses. The laboratory takes a myriad of approaches including cell biology, molecular biology, genetics, genomics, murine modeling, genetic engineering, hematopoietic stem cell manipulation, biochemistry, signal transduction, and bioinformatics. A variety of genetically engineered murine cell lines, recombinant genes, and recombinant proteins have been produced.

Current Research Objectives:

To elucidate the cellular and molecular processes involved in allergic responses in the gastrointestinal tract and lung using a variety of approaches including novel models of allergic responses in-vivo and in-vitro.
To test the importance of key molecule including chemokines and cytokines in vivo using transgenic and gene-targeted mice.
To biochemically characterize the transcriptional programs, regulating molecules and signal transduction mechanisms responsible for eosinophil development and activation.
To test the importance and blockade of these pathways in patients with inflammatory diseases such as eosinophilic esophagitis and hypereosinophilic syndromes.
To identify genes and key check points that predispose to eosinophilic disorders.

Specific Research Projects:

Role of eotaxins and CCR3 in IL-13-induced asthma – The major goal of this project is to define the individual and combined roles of eotaxin-1, eotaxin-2, IL-5, and CCR3 in IL-13-elicited lung responses.
Mechanistic analysis of eosinophilic esophagitis – The major goal of this project is to understand the development of experimental eosinophilic esophagitis in mice by exploring the mechanism of antigen sensitization and dendritic cell involvement.
Epithelial-derived eotaxin-3 and eosinophilic esophagitis – The major goal of this project is to understand the role of eotaxin-3 in human eosinophilic esophagitis. Studies involve cellular distribution of eotaxin-3 and its receptor, the role and mechanisms of an eotaxin-3 SNP in disease pathogenesis, and the effect of glucocorticoid therapy on eotaxin-3 expression and esophageal transcript profiles.
IL-13 and eosinophilic esophagitis – The major goal of this project is to identify the expression and role of IL-13 in eliciting human eosinophilic esophagitis and in experimental eosinophilic esophagitis in mice.
IL-13 Associated Eosinophil Lung Responses –The major goal of this project is to broaden our understanding of asthma associated lung pathology aiming to clarify the unique and comparative effects of interrupting IL-4, IL-13 and/or their receptors in asthma.
Regulation of Gastrointestinal Eosinophils – The major goals of this grant are to analyze gastrointestinal eosinophils at baseline and during Th2-associated allergic responses in the gastrointestinal tract.
Candidate Gene Approach for Eosinophilic Esophagitis – The major goal is to take a candidate gene approach to identify genetic risk factors for EE and to gain molecular insight into disease pathogenesis.
Novel Genetic and Therapeutic approaches focusing on siglec-8 for the diagnosis and treatment of human idiopathic eosinophilic disorders – This is a collaborative grant with Dr. Bruce Bochner at Johns Hopkins University and the major goal is to explore the role of Siglec-8 in human eosinophilic disorders taking genetic and structure-function approaches.
The role of CREB binding protein (CBP) in Eosinophilic Esophagitis – The major goal of this project is to analyze the role of CREB binding protein (CBP) in the pathogenesis of eosinophilic esophagitis.

Amal H. Assa'ad, MD
Dr. Assa'ad is currently conducting clinical research. Her main area of research is food allergy and asthma. Her research currently addresses the occult effect of allergic sensitization to foods on the bronchial hyperresponsiveness seen in asthmatic and the genetic basis of food allergy. She also participates in multicenter pharmaceutically sponsored research of investigational new drugs in asthma and immunodeficiencies. She is working with the basic research investigators in the division on establishing a translational research program that will bring basic research to the beside in the area of atopic and eosinophilic diseases.

Carine Blanchard, PhD
Dr. Blanchard's primary research is focused on the molecular pathogenesis involved in food allergy related disorders. To better understand the molecular mechanisms underlying these diseases, her laboratory has studied eosinophilic esophagitis (EE) and murine models. Dr. Blanchard and her colleagues recently discovered that these Th2 diseases and models were characterized by an increased expression of the secreted protein TSG6 mRNA, tumor necrosis factor induced gene 6. As a result of this observation, Dr. Blanchard has focused on discovering the regulation of expression and role of TSG6 in food allergy related responses. Starting in July 2008, this work was supported by a 2 year NIH R21 grant and a one year award from Digestive Health Center. Dr Blanchard was also awarded a 2009 Hope grant from the American Partnership for Eosinophilic Disorders (APFED) for junior faculty to study the expression of human uroplakin 1B upregulation in the human food allergy related disease, eosinophilic esophagitis.

J. Pablo Abonia, MD
Dr. Abonia provides the bulk of the clinical allergy care for patients with eosinophilic disease. He is currently involved in a multicenter clinical research trial of anti-IL5 (reslizumab) for patients with eosinophilic esophagitis. His research focuses on mining the research databanks (patient characteristics, tissue samples, RNA, and DNA) to elucidate the mechanisms, diagnosis and treatment of eosinophilic esophagitis. He is particularly interested in the role of mast cells in eosinophilic esophagitis.

Simon P. Hogan, PhD

Dr. Hogan's research group is focused on understanding the effect of allergic and non-allergic inflammatory reactions on intestinal function. In particular, we study the effects of inflammation (T-cell and innate) on gastrointestinal function in food-induced anaphylaxis and Inflammatory bowel diseases. Our approach integrates basic, translational and clinical research streams with advanced molecular and cellular biological techniques and state-of-the-art mouse models of disease. We hope that by delineating the cellular and molecular inflammatory cascades involved in food-induced anaphylaxis and IBD, we will be able to better understanding the functional consequences of intestinal inflammatory diseases. Furthermore, it is hoped that these studies will identify new therapeutics targets for the treatment and prevention of these debilitating diseases.

Research Projects
The group has a wide variety of projects that focus on basic mechanisms underlying the immunopathogenesis of Food-induced anaphylaxis and IBD:

Food-induced Anaphylaxis Research Program:
•   Defining the role of mast cell derived mediators in secretory diarrhea-assoicated with food anaphylaxis.
•   Define the relationship between increased intestinal IL-9 and mast cells in food-induced anaphylaxis.
•   Defining the effect of elevated intestinal interleukin-13 on small bowel structure and function.
•   Delineate the role of Sphingosine 1-phosphate in the regulation of intestinal mast cells and experimental intestinal anaphylaxis.
•   Define the role of mast cell derived chymase in homeostatic regulation of intestinal permeability.

Inflammatory Bowel Disease Research Program:
•   Identify the cellular source of eotaxin-1 in pediatric UC.
•   Define the cellular and molecular mechanisms involved in eosinophil activation, survival, recruitment and effector function in
     Inflammatory bowel diseases (Crohns Disease and Ulcerative Colitis).
•   Define the role of Paired immunoglobulin receptor-B in intestinal inflammation and colonic injury.

Michelle B. Lierl, MD
Dr. Lierl's research involves studying "A randomized trial to reduce environmental tobacco smoke exposure in children with asthma". Her role in this study is as an advisor for study design and implementation, trainer for the field staff in asthma assessments, spirometry and exhaled NO collections, and the actual measurement of exhaled NO concentrations. She is studying the usefulness of exhaled NO as a predictor of the development of post-viral asthma, in infants with bronchiolitis. She is also getting ready to embark on a study utilizing a telemedicine approach to asthma management in the school setting. Dr. Lierl is also conducting a study of the inflammatory processes in Pharangytis and Cervical Adenitis Syndrome (PFAPA), and the responses of PFAPA to treatment with Singulair.

Anil Mishra, PhD
Dr. Mishra's scientific objective includes elucidating the mechanism for recruitment of inflammatory cells into mucosal allergic tissue. He is aiming to elucidate the mechanisms involved in the development of hypersensitivity responses in the esophagus and the connection between pulmonary and esophageal inflammation. He developed first murine model of eosinophilic esophagitis. His research interest also includes in understanding the mechanism of aeroallergen-induced allergic responses in the lung and lower gastrointestinal tract. Dr. Mishra’s research is funded by NIH.

Kimberly Risma, MD, PhD
Dr. Risma's laboratory is focused on the molecular and cellular bases of primary disorders of immune deficiency and dysregulation, especially as it relates to lymphocyte cytotoxicity. Cytotoxic T cells and natural killer cells contain specialized secretory granules that contain perforin, a toxic molecule that can damage the membrane of target cells, and granzyme B, a protease that is delivered by perforin to induce apoptosis in the target cell. Perforin-mediated cytotoxicity is critical for both immunologic defense and immune regulation. Importantly, defects in the perforin gene have been identified as a genetic cause of a fatal inflammatory disease of early childhood: familial hemophagocytic lymphohistiocytosis type 2 (FHLH2). There is currently no molecular or structural model to predict the functional impact of missense mutations in perforin. We are delineating the pathologic consequences of missense mutations in perforin identified in patients with FHLH2. We utilize cell model systems to study proteolytic maturation, secretion, lipid binding, and stability of mutant perforins. Our studies will advance the current understanding of the pathogenesis of FHLH2, our ability to predict genotype/phenotype correlations, and the basic cellular mechanisms underlying perforin-mediated, lymphocyte cytotoxicity.

Yui-Hsi Wang, PhD
Dr. Wang’s laboratory is focused on exploring the role and regulation of dendritic cells and TH2 memory T cells that contribute to the progression and persistence of allergic disorders in both humans and mouse disease model. We are particular interested in understanding how the inflammatory mediators produced by the activated innate immune systems regulate the acquired immune responses, which may lead to the heterogeneity of allergic diseases such as asthma and food allergy. Currently, we are investigating the cellular and molecular mechanisms underlying the maintenance, regulation, and diversification of TH2 memory T cells during allergic inflammation. The long term goal is to identify and target allergen-specific TH2 memory cells and their maintaining mechanisms for developing more effective therapy for human allergic diseases.

Nives Zimmermann, MD
Dr. Zimmermann's laboratory is mainly focused on deciphering mechanisms of allergic diseases, primarily asthma. Eosinophils are the hallmark cell of allergic inflammation, including asthma. The long-term goals of the laboratory are 1) to understand the mechanisms of eosinophilia with the ultimate aim of changing the outcome of eosinophil-mediated diseases and 2) to understand the mechanisms of lung inflammation, in homeostasis and allergic disease. A variety of approaches are undertaken, including animal modeling and ex vivo cell and molecular biology. Currently we are focused on molecular understanding of eosinophil survival in allergic inflammation and asthma; in other words, why are eosinophils recruited and why do they stay and lead to disease in some people and not in others.

Li Zuo, MD
Dr. Zuo’s research interests include the understanding of food allergy mechanism and the exploration of new therapeutic options for the treatment of food allergy. One of Dr. Zuo’s research goals is to study the factors involved in the increased peanut allergy prevalence in the western society. Dr. Zuo is also involved in the eosinophilic esophagitis (EE)research which is a unique disorder with a strong food allergy component. For the EE study, Dr. Zuo has demonstrated that IL-13, an important Th2 cytokine, plays an important role in the pathogenesis of EE, in an IL-13 over-expressed mouse model. The effect of IL-13 on EE includes the induction of esophageal eosinophilia and tissue remodeling.

Allergy and Immunology

Faculty Research

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