T cells mediate immune responses against self and non-self antigens (Ags), including innocuous environmental Ags, which are sometimes erroneously interpreted as 'dangerous'. Misguided responses by Th2 polarized effector T cells (Teff) against certain environmental Ags, called allergens, promote the formation of humoral and cellular inflammatory responses that precipitate clinical symptoms, which become manifest as various forms of allergy or asthma.<P> Current clinical practice employs therapeutic strategies to tolerize allergic patients against specific allergens, indicating that pre-existing pathological Th2 responses can be 're-educated' resulting, at least in some cases, in permanent cures. However, current immunotherapy schemes typically require many months of continuous treatment, are unsuccessful in a sizable fraction of patients and carry the risk of adverse events, particularly anaphylaxis.<P> Project 3 proposes to explore the use of induced tolerogenic dendritic cells (itDC) as an alternative strategy to rapidly achieve allergen-specific immunological tolerance in individuals suffering from allergic asthma or food allergy. The rationale for this project is based on the fact that T cell function is controlled by dendritic cells (DC), which acquire and process Ags and, depending upon their maturation and differentiation status, instruct Agspecific T cells either to mount an effector response or to develop tolerance.<P> A body of preliminary data indicates that short-term exposure of murine as well as human DC to rapamycin and transforming growth factor B (TGFB) coverts the cells into itDC. Preliminary in vitro and in vivo experiments suggest that Ag-pulsed itDC exert tolerogenic effects on Ag-specific conventional T cells a) by converting them into Foxp3+ regulatory T cells (Treg) and b) by deleting Teff at sites of Ag challenge.<P> In light of these findings, the hypothesis will be tested that itDC may be useful to treat T cell-dependent allergic diseases. To achieve this goal, Aim 1 will establish whether and to what extent itDC exert therapeutic effects in mouse models of Agdriven allergic asthma and food allergy. Aim 2 will generate critical clues regarding the clinical translatability of findings in murine models to human food allergy and allergic asthma by systematically exploring the capacity of patient-derived DC to induce tolerogenic responses in autologous T cell subsets. <P>These experiments will be performed in close synergy with Projects 1 and 2 and rely on technology, materials and support from each Core of this Program. If our hypothesis can be proven correct, our objective will be to translate the itDC technology into a clinical platform for cellular therapy of food allergy and asthma.
Public Health Relevance: T cell-mediated allergic disorders, such as allergic asthma and food allergy, are chronic debilitating diseases that can cause severe human suffering and place a substantial economic burden on individuals and society. Current treatment options have limited efficacy and are often not curative. This project seeks to address a major unmet medical need by exploring the utility of itDC as a new therapeutic platform that may offer a safe and efficacious alternative to treat and potentially cure allergic diseases.