Unique populations of lung mast cells are required for antigen‐mediated bronchoconstriction

Abstract

Studies in both human and mouse indicate that mediators released by mast cells can lead to bronchoconstriction, and thus these are important effector cells in lifethreatening anaphylaxis. Much of our understanding of the various functions of mast cells emanates from the study of mice lacking these cells, particularly mice carrying mutations in the tyrosine kinase gene Kit. Definitive evidence for the role of mast cells in the altered immune response requires the demonstration that this response can be normalized by reconstitution of the mice with cultured bone marrow-derived mast cells (BMMCs). While many mast cell niches can be restored with BMMCs, this has not been demonstrated for mast cells present in the airways of the lung, cells poised to mediate bronchoconstriction during allergic responses. To determine if mast cell-deficient Kit(Wsh/Wsh) reconstituted lines are an appropriate model for the study of the role of these cells in bronchoconstriction associated with allergic responses. Kit(Wsh/Wsh) mice were reconstituted with either whole bone marrow (WBM) or BMMCs and responses to IgE-mediated mast cell activation were determined; including systemic hypothermia, mediator release, and bronchoconstriction in anaesthetized, mechanically ventilated animals. Engraftment of Kit(Wsh/Wsh) mice with WBM and BMMCs results in reconstitution of the central airways with mast cells. While the treatment of the two groups of animals resulted in systemic changes when challenged with IgE/Ag in a model of passive anaphylaxis, bronchoconstriction was observed only in kit(Wsh/Wsh) animals, which had received a bone marrow transplant. While BMMCs can populate the lung, they cannot restore IgE/Ag-mediated bronchoconstriction to mast cell-deficient animals. This suggests that the mast cell population, which mediates this function, may be unique, and to fill this niche in the lung cells must undergo a specific developmental programme, one that is no longer available to cultured mast cells.