Host Factors Regulating Allergic Responses to Aspergillus

Children'S Hosp Pittsburgh/Upmc Hlth Sys, Pittsburgh PA

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Abstract

Aspergillus fumigatus is a ubiquitous fungus that can cause allergic bronchopulmonary aspergillosis (ABPA)[unreadable] in susceptible individuals. The populations at high risk for this disease include patients with cystic fibrosis[unreadable] (CF) and severe asthma. Together, alveolar macrophages, neutrophils and dendritic cells serve to promote[unreadable] both inflammatory and protective responses against Aspergillus. Our preliminary data on mechanisms that[unreadable] trigger Aspergillus-induced pathology suggest important roles for specific cell surface and secreted[unreadable] molecules that together modulate the immune response to Aspergillus. These include cell surface molecules[unreadable] such as dectint on macrophages and DCs, lung expressed surfactant proteins (collectins) and specific[unreadable] cytokines/chemokines (RANTES and IL-12p40) secreted by Aspergillus-stimulated DCs. Also, an early[unreadable] pathogen-expressed molecule, Aspfl, was a poor allergen in vivo even in the context of strong Th2-skewing[unreadable] adjuvants. Interestingly, peptides derived from Aspfl were reported to be tolerogenic in mice. Collectively,[unreadable] these observations lead us to hypothesize that a) interactions between different cell types involving beta[unreadable] glucan on Aspergillus and dectint on host cells and immune defense molecules such as surfactants play an[unreadable] important role in inducing imrhunomodulatory cytokines and chemokines that induce the characteristic[unreadable] eosinophilic inflammation in ABPA and b) tolerance induction to Aspergillus can be achieved using specific[unreadable] pathogen Ags that together with innate defense mechanisms is an important mechanism that prevents[unreadable] unwarranted immune responses against the pathogen. To test these hypotheses we will:[unreadable] Aim I. Characterize the effect of A. fumigatus on the adaptive immune response and its dependence on[unreadable] specific cell surface components on cells of the immune system (dectin-1 and TLR2).[unreadable] Aim II. Determine the effect of surfactant D on Aspergillus-induced immune responses.[unreadable] Aim III. Determine whether repeated exposure to immunodominant peptides derived from Aspfl can induce[unreadable] tolerance to the whole pathogen.[unreadable] Thus, using a variety of molecular, biochemical and immunological approaches and genetically altered mice,[unreadable] our studies will focus on interactions between the pathogen, A. fumigatus, and the host in the induction and[unreadable] prevention of allergic responses to Aspergillus.