We aim to investigate the mechanisms of desensitization and long-term tolerance associated with sublingual and subcutaneous allergen immunotherapy (SLIT and SCIT, respectively). The proposed work will include investigation of allergen-specific T cells enriched and analysed freshly ex vivo using tetramers labelled with grass pollen immunodominant epitopes as well as with transcriptome analysis. Using these technologies we will primarily investigate mechanisms of SLIT, with subjects receiving SCIT or placebo acting as positive and negative control groups, respectively. This work is to be performed in the context of an Immune Tolerance Network funded randomized double-blind, double dummy, controlled clinical trial (SLIT vs. placebo, SCIT vs. placebo). Although the primary focus and endpoint of this trial relates to the effects of SLIT vs. placebo, it will provide an unparalleled opportunity to examine both forms of treatment and to correlate immunologic and clinical outcomes. Investigations will be performed both during the 'desensitisation phase'(i.e. while patients are actively receiving immunotherapy) and during the 'tolerance phase'i.e. after discontinuation of treatment. This work also has the potential to inform selection of novel biomarkers for effective SLIT and SCIT. We hypothesize that grass pollen immunotherapy (SLIT and SCIT but not placebo) will: 1. Reduce the frequencies of circulating grass pollen tetramer-reactive T cells. 2. Alter phenotypes of grass pollen tetramer-reactive Th2 cells in favor of antigen-specific Tregs and Th1 cells. 3. Induce immunologic changes that persist following immunotherapy discontinuation. 4. Modify transcriptional profiles of allergen-specific T cells, giving rise to potential new biomarkers for effective tolerization.

Public Health Relevance

Hay fever affects around 1 in 5 Americans;many respond poorly to treatments like antihistamines, but immunotherapy ('allergy shots') can be very effective. A new type of immunotherapy has been developed that is taken under the tongue as a tablet instead of by injection. We will test if this works by changing the immune system in a group of people receiving these new tablets as well as in people receiving normal shots.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095074-03
Application #
8497596
Study Section
Special Emphasis Panel (ZAI1-LGR-I (J2))
Program Officer
Minnicozzi, Michael
Project Start
2011-08-15
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$366,285
Indirect Cost
$107,385
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Wambre, Erik; DeLong, Jonathan H; James, Eddie A et al. (2014) Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J Allergy Clin Immunol 133:872-9.e7
Archila, L D; DeLong, J H; Wambre, E et al. (2014) Grass-specific CD4(+) T-cells exhibit varying degrees of cross-reactivity, implications for allergen-specific immunotherapy. Clin Exp Allergy 44:986-98