Asthma is an inflammatory lung disease often triggered by inhalation of protein allergens. Because of the central role of T cells in asthma, as with other allergic diseases, prevention may lie in treatments that enhance tolerance mechanisms. Injection of allergens subcutaneously has been used for many years as a treatment, called specific-allergen immune therapy (SIT or AIT), with the goal of inducing long-term tolerance. However, although SIT/AIT can undoubtedly be efficacious in some patients, it is a lengthy, inefficient, and often ineffective treatment, warranting new approaches that may quickly induce a state of tolerance and one that is maintained over time. As the development of inducible regulatory T cells (iTreg) and the concomitant deletion of memory T cells may be key to tolerance, new insights into the molecular control of these cells may then reveal therapeutic targets that can be combined with allergen treatment. We have shown in a mouse model of asthma that inhalation of pure protein antigen induces two iTreg populations, Foxp3+LAP- and Foxp3-LAP+ CD4 cells, that both can suppress Th2-driven allergic lung inflammation and protect against developing subsequent lung disease. Moreover, we identified a lung antigen-presenting cell (APC) that may be responsible for inducing these iTreg. We have further shown that signals through two pattern recognition receptors (PRR), TLR4 and Nod2, expressed in the lung, directly antagonize development of the iTreg and instead favor the development of pathogenic Th2 cells. Most importantly, these PRR drive the lung response through two cytokines, TSLP and IL-25, and a costimulatory member of the TNFR superfamily OX40L. Whether allergens elicit the same molecular signature to oppose tolerance is unclear, but we have found that generation of airway iTreg is inhibited by two extracts that are used for SIT in asthmatics and contain allergens associated with asthma, from Dermatophagoides pteronyssinus, a house dust mite (HDM), and from Aspergillus fumigatus, a fungus. Tolerance in allergic and asthmatic individuals also has to counter activities of pre-existing memory T cells We have further identified OX40L and another TNF costimulatory family ligand, LIGHT, as strong regulators of memory T cells that drive their clonal expansion and survival. Our hypothesis is then that long-term and effective tolerance will only be achieved to allergens in previously sensitized individuals if several of these molecules, and cytokines that synergize with these molecules, are coordinately suppressed. This proposal will determine the molecular signature elicited by several common human allergens, and test whether manipulating these cytokines and costimulatory ligands, and APC that drive iTreg induction, will be key to promoting tolerance in sensitized individuals during allergen immunotherapy.

Public Health Relevance

Costimulatory molecules and cytokines are central to most immune responses, but may differ depending on the antigen that is driving the immune response. We have identified several TNF family molecules and innate cytokines that synergize together to promote asthmatic lung inflammation and suppress tolerance mechanisms. Knowledge of whether these, or related, molecules are induced by human allergens, and whether there is a common immunological signature induced by allergens that inhibits regulatory T cells and promotes damaging T cells, is then important for understanding the pathogenesis of human allergic diseases such as asthma. Identifying the molecules involved in cross-talk between T cells and APC in the lung may allow the rationale design of prophylactic treatment together with conventional allergen immunotherapy to promote the induction of regulatory T cells and block pathogenic T cells. This information could protect individuals against developing or re-developing allergic disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Davidson, Wendy F
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La Jolla Institute
La Jolla
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Mehta, Amit K; Duan, Wei; Doerner, Astrid M et al. (2016) Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. J Allergy Clin Immunol 137:278-88.e6
Mehta, Amit K; Gracias, Donald T; Croft, Michael (2016) TNF activity and T cells. Cytokine :
Duan, Wei; Croft, Michael (2014) Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells. Ann Am Thorac Soc 11 Suppl 5:S306-13
Soroosh, Pejman; Doherty, Taylor A; Duan, Wei et al. (2013) Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J Exp Med 210:775-88
Croft, Michael; Benedict, Chris A; Ware, Carl F (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147-68