Antiinflammatory and immunosuppressive functions of mast cells

Through the release of biologically active products, mast cells function as important effector and immunoregulatory cells in diverse immunological reactions and other biological responses; for example, mast cells promote inflammation and other tissue changes in immunoglobulin E (IgE)-associated allergic disorders, as well as in certain innate and adaptive immune responses that are thought to be independent of IgE. Despite the mast cell's well-deserved reputation as a promoter of inflammation, others and we have used bone marrow-derived cultured mast cell (BMCMC) engrafted mast cell-deficient c-kit-mutant mice (so-called "mast cell knock-in" mice) to show that mast cells can also have important antiinflammatory and immunosuppressive functions in vivo. An early study showed that mast cells can contribute to susceptibility to ultraviolet B (UVB)-induced immunosuppression in one model of contact hypersensitivity (CHS), through effects mediated at least in part by histamine. Subsequently, it was reported that mast cells can mediate negative immunomodulatory effects following Anopheles mosquito bites, and in peripheral tolerance to skin allografts; however, the mechanism(s) by which mast cells mediate immunosuppressive functions in these two studies remains to be elucidated. Finally, we showed that mast cells and mast cell-derived IL-10 can limit the magnitude of and promote the resolution of certain CHS responses, and suppress the inflammation and skin injury associated with innate cutaneous responses to chronic low-dose UVB irradiation. This chapter outlines the generation of BMCMCs, a powerful model system commonly used to: (1) identify potential mast cell mediators in vitro; (2) study the mechanisms of mast cell activation and mediator release in response to specific stimuli in vitro; and (3) engraft mast cell-deficient mice to study the effector and immunoregulatory roles of mast cells or specific mast cell mediators in diverse immunological responses in vivo.