IMMUNOLOGY AND INFLAMMATORY DISEASES
Shreffler Laboratory: Wayne Shreffler, MD, PhD
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Mechanisms of Immune Reactivity or Tolerance to Allergens in Humans
The Shreffler Laboratory at Massachusetts General Hospital research program involves a combination of approaches, primarily with human samples and often in conjunction with clinical interventional or observational studies, to interrogate both the innate and adaptive immune responses to major dietary and aeroallergens.
Working together with leading clinical investigators around the world as part of the Consortium for Food Allergy Research and the Inner City Asthma Consortium and the newly established Food Allergy Research Center at Mass General, we are adapting the use of polychromatic flow cytometry and peptide microarray-based humoral immune profiling and systems biology approaches to uniquely characterize the phenotype and function of allergen-specific T and B cell responses and the regulations of effector cells in pediatric food allergy and asthma.
Equally important is our effort to understand the mechanisms that influence early immune fate decisions to allergens and the intrinsic properties of those allergens that facilitate an allergic response and we are studying this in human and murine model systems.
Clinical Reactivity or Tolerance to Mouse Allergen
There is poor understanding of how natural allergen exposure relates to the ensuing allergen-specific immune responses and how atopic disposition modifies allergen exposure-immune response relationships. In collaboration with Drs. Elizabeth Matsui at The Johns Hopkins School of Medicine and Beverly Paigen at the Jackson Laboratory, we are using an occupational model of allergen exposure to test the hypothesis that high levels of natural exposure to mouse allergen induces regulatory responses to the major mouse allergen, Mus m 1, and ultimately protects against clinical allergy.
Mechanisms of Peanut Adjuvanticity
Allergy to peanut (Arachis hypogaea) tends to be persistent and severe, and it represents an increasingly prevalent public health problem, affecting more than three million Americans. We are unraveling the mechanisms by which peanut seed constituents directly activate innate immune cells to promote a strong and persistent allergic response in susceptible individuals.
Basophil Activation and Regulation
Effective allergen-specific immunotherapy is known to induce several immunological changes that correlate well with clinical efficacy, including increased levels of allergen-specific IgG and decreased effector cell (e.g., basophil, mast cell) responsiveness. These changes precede any decrease in specific IgE and this correlation has led to the hypothesis that they are key targets of immune regulation leading to tolerance. Basophils are ideal for the study of immunotherapy mechanisms because they are predominantly present in the peripheral blood, can be readily stimulated ex vivo, share expression of both receptor and signaling pathway molecules with mast cells and can be measured by flow cytometry with minimal manipulation. We study the mechanisms of basophil anergy (induced hyporesponsiveness) and whether such anergy contributes to clinical improvement in human subjects receiving immunotherapy for peanut allergy.
Clonal Diversity of B cell Response to Allergens
Individuals with immediate hypersensitivity have a pathological immune response to ubiquitous antigens characterized by the failure of immune tolerance and the production of specific IgE. There is a spectrum of immunity to proteins encountered at mucosal sites ranging from non-sensitized, to sensitized, to transiently allergic or persistently allergic individuals. The natural history of this immune response and how it varies between these groups is poorly understood. We hypothesize that increased allergen-specific antibody diversity, avidity and IgE/IgG4 ratio are markers of Th2 immune progression and will correlate with reaction severity and allergy persistence. We have developed a microarray-based immunoassay for the analysis of allergen-specific antibody diversity to test this hypothesis in food allergy and occupational asthma.
Wayne Shreffler, MD, PhD
Principal Investigator, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital
Director, Food Allergy Center, Massachusetts General Hospital
Chief, Pediatric Allergy and Immunology, MassGeneral Hospital for Children
Associate Professor of Pediatrics, Harvard Medical School
Victoria Martin, MD
Bert Ruiter, PhD
Yamini Virkud, MD, MPH
David Pyle, MD
Clinical Research Coordinators