A number of unique diagnostic and therapeutic advances in the area of human allergic disease are currently on the horizon. Ironically, our understanding the fundamental immune processes governing allergic disease pathology and treatment is still poorly understood. Anti-IgE, oral immunotherapy and CpG-based technologies have emerged as exciting treatment options for asthma, severe allergic rhinitis and food allergy. Preliminary evidence indicates that the immature human dendritic cell may be a critical target for these therapies (as well as classical subcutaneous immunotherapy). However, the mechanisms are not known. Studies have shown that dendritic cells express the high affinity IgE receptor (Fc(RI) and that this receptor correlates with serum IgE levels and allergic status. In addition, recent evidence has shown that the IgE receptor and the toll-like receptor may counter-regulate one another on dendritic cells. While it has long been understood that IgE mediated responses dominate in allergic disease, new evidence indicates that dendritic cells from allergic subjects have impaired toll-like receptor (TLR) mediated responses. These findings have led to the hypothesis that cross-regulatory mechanisms may exist between innate (TLR) and adaptive (IgE) immune receptors and their function on dendritic cells that may contribute to allergic disease manifestations. It has not yet been established whether there is a clinical correlate to the IgE/TLR interactions noted in vitro. For example, are TLR/IgE receptors on dendritic cells from allergic subjects phenotypically and/or functionally different from those of non-allergic individuals? Do dendritic cells obtained from one allergic disease population such as allergic rhinitis function distinctly from dendritic cells obtained from food allergic individuals or asthmatics? Does immunotherapy affect dendritic cell function or IgE/TLR receptor interactions? In this proposal we aim to define and contrast the major IgE and TLR receptor mediated responses in dendritic cells in three distinct disease groups namely;mild-moderate persistent asthma, peanut allergy and moderate-severe allergic rhinitis. We will compare the mechanisms governing dendritic cell function in each of these ailments in an effort to help uncover the pathologic basis of allergic disease. In doing so we aim to identify significant targets for therapy- some of which may already be exploited with classical and experimental versions of allergen immunotherapy. We will dissect the nature of the IgE receptor on human dendritic cells and construct a model for allergen interactions. We will analyze components of dendritic cell signaling events. Finally, we will specifically investigate dendritic cell immune mechanisms that are essential to clinically successful allergen immunotherapy. The goal of this project is to expand our knowledge of human dendritic cell immune function as it relates to allergic disease and mechanisms of allergen immunotherapy. This work will ultimately contribute to better diagnosis and treatment of food allergy, allergic rhinitis and asthma.

Public Health Relevance

The goal of this project is to expand our knowledge of human dendritic cell immune function as it relates to allergic disease and mechanisms of allergen immunotherapy. This work will ultimately contribute to better diagnosis and treatment of food allergy, allergic rhinitis and asthma.

Agency
National Institute of Health (NIH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI080716-06
Application #
8660021
Study Section
Transplantation Biology &Immunology-2 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218