The balance between pro-inflammatory and anti-inflammatory signaling is a prerequisite for successful host/fungal interaction in aspergillosis. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases and limit protective antifungal immune responses. The newly described Th17 developmental pathway may play an inflammatory role previously attributed to uncontrolled Th1 cell responses. The capacity of regulatory T cells (Tregs) to inhibit aspects of innate and adaptive antifungal immunity, including functional Th17 antagonism, is required for protective tolerance to Aspergillus. The indoleamine 2,3-dioxygenase (IDO) and thyptophan catabolites contribute to such a homeostatic condition by providing the with host immune defense mechanisms adequate for protection, without necessarily eliminating fungal pathogens—which would impair immune memory—or causing an unacceptable level of tissue damage. The IDO mechanism has revealed an unexpected potential in the control of inflammation, allergy and allergic airway inflammation, all conditions in which plasmacytoid dendritic cells could have a protective function. IDO expression is paradoxically up-regulated in patients with allergy or autoimmune inflammation, a finding suggesting the occurrence of a homeostatic mechanism to halt ongoing inflammation. A unifying mechanism linking antiinflammatory Tregs to tolerogenic Tregs via IDO appears to be at work in response to the fungus and is consistent with the revisited "œhygiene hypothesis" of allergy in infections—that is, an early reduction in microbial burden may predispose to allergy. IDO has a unique and central role in this process acting as both an executor of the effector phase of antiinflammatory Tregs and an inducer of tolerogenic Tregs. Recent data have confirmed the protective role of the IDO/Tregs axis in fungal allergy. In this model, modulation of tryptophan catabolism via the glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand, GITRL, inhibited Th2-cell responses and allergy and induced the expression of Foxp3+ Tregs through mechanisms dependent on IDO induction by components of the noncanonical NF-954;B signaling pathway. Thus induction of IDO could be an important mechanism underlying the anti-inflammatory action of corticosteroids. Together, these new findings provide a molecular connection between the failure to resolve inflammation and lack of antifungal immune resistance and point to strategies for immune therapy of fungal infections that attempt to limit inflammation in order to stimulate an effective immune response.
Full conference title:
3rd Advances Against Aspergillosis
- AAA 3rd (2008)