In keeping with the noted ability of chitin to stimulate the production of type 1 cytokines, and the known ability of type I cytokines to inhibit type 2 inflammation [24
], several lines of evidence suggest that chitin can regulate type 2 immune responses. Initially, Shibata et al.
demonstrated that orally administered chitin inhibited allergen-induced IgE production and lung inflammation in a ragweed-immunized allergic animal model [26
]. In these experiments the production of type 2 cytokines by allergen stimulated spleen cells, was also decreased by the addition of chitin to in vitro
culture and, the inhibitory effects were shown to be mediated by IFN-γ produced by NK cells and ragweed-specific Th1 cells. In a separate study, the same group of investigators demonstrated that chitin is a strong Th1 adjuvant that up-regulates heat-killed Mycobacterium bovis Calmette-Guerin bacillus-induced Th1 immunity, and down regulates mycobacterial protein-induced Th2 immunity [27
]. Chitin micro-particles (CMP) have also been shown to be Th1 adjuvants in the induction of viral specific immunity [28
]. Direct instillation of CMP into the lung also significantly down-regulated allergic responses to Dermatophagoids pteronyssinus
(Der p) and Aspergillus fumigatus
including IgE levels, IL-4 production, peripheral eosinophilia, airway hyper-responsiveness, and lung inflammation while increasing the levels of IL-12, IFN-γ and TNF [29
]. Ozdemir et al.
also demonstrated that microgram quantities of CMP prevented and ameliorated the histopathologic changes in the airways of “asthmatic” mice [30
]. In accord with these findings, intranasal application of water soluble chitosan also significanlty attenuated Dermatophagoids farinae
(Der f)-induced lung inflammation and mucus production [29
]. When viewed in combination, these studies strongly support the contention that chitin can have inhibitory effects on the development of adaptive type 2 allergic responses. Further support for this concept comes form recent studies that demonstrate that thymic stromal lymphopoietin (TSLP) and arginase I play critical roles in Th2 polarization and tissue remodeling responses respectively [31
] and that they are both inhibited at sites of allergen-induced inflammation by water soluble chitosan [33
]. It is important to point out however that, there is also data that suggests that chitin can also augment Th2 responses. This includes the data noted above by Reese et al
. that highlights Type 2-like innate immune responses elicited by chitin beads. It also includes studies from our laboratory that demonstrate that appropriately sized chitin fragments stimulate macrophage IL-17 and IL-23 production via a TLR-2-dependent and TLR-4-independent mechanism [34
] and that chitin can be a potent adjuvant in the ovalbumin mouse model of Th2 inflammation (Da Silva CA and Elias JA, unpublished observation). In combination, these studies suggest that chitin may not have a unidirectional effect on Th2 immunity in vivo
. However, the experimental and biologic factors that explain the different responses that have been seen have not been adequately defined.