The laboratory's research is focused on understanding cellular and molecular mechanisms contributing to pathogenesis, regulation and functions of the adaptive immune system in disease pathways. Using techniques developed in the lab, we take advantage of the selective expression of CD154 marker after short stimulation to directly identify and characterize ex vivo antigen-specific CD4+ T cell responses at the single cell level. The lab studies focus on atopic allergy, atopic asthma, cancer and type 1 diabetes. The overarching aim of the lab is to generate the knowledge necessary to inform better vaccine design and to develop clinically meaningful biomarkers. Specific research emphases include:
Currently, the lab is focusing on the identification of immunological signatures for allergic disease. We have identified a distinct TH2 subset involved in allergic disease that is virtually absent in non-allergic individuals. This subset is characterized by the unique expression of five T cell surface markers and includes the vast majority of allergen-specific TH2 cells. As such, we denote cells with this surface marker expression as the TH2A subset. We are currently examining the pathophysiologic meaning of the allergic T cell signature. We are also evaluating the ability of this pathogenic footprint to reflect and predict an underlying allergic disease process.
Figure: TH2A cells are a unique TH2 subset confined to allergic individuals, encompassing the vast majority of pathogenic allergen-specific CD4+ T cells. Further detailed studies focusing on the TH2A cell subset may prove useful in the diagnosis, molecular characterization or the discovery of novel therapeutic targets to enhance the power of allergen vaccines.
Immunopathogenesis of Allergic Disorders
The balance between pathogenic and protective allergen-specific CD4+ T cells appears to be decisive in the development of allergic disease or a healthy immune response. We have found that CD27 expression in allergic individuals defines two functionally distinct allergen-specific T cell subsets - with the smaller subset expressing and the larger lacking - CD27 expression. In contrast, protective responses in non-atopic individuals are associated with CD27+ allergen-specific T cells. We therefore hypothesize that CD27 expression distinguishes protective (CD27+) from pathogenic (CD27-) allergen-specific CD4+ T cells. We are currently examining the phenotypic and functional properties of CD27- and CD27+ allergen-specific CD4+ T cells and investigating their differential capacity to help B cells.
Mechanisms of Allergen-Specific Immunotherapy
Allergen-specific immunotherapy (ASIT) is the only disease-modifying treatment for allergy. However, effective, limited understanding of the immunologic mechanisms underlying ASIT has hampered its broad applicability and the development of novel targeted vaccines with improved efficacy and safety. We have shown that allergen-specific TH2 cells are more susceptible to apoptosis than CD27+ (protective) allergen-specific CD4+ T cells. We are now testing the hypothesis that preferential allergen-specific TH2 cell deletion represents a crucial factor involved in the restoration of peripheral tolerance to allergen during ASIT. If successful, these results will guide development of more effective therapies for allergic disease.