Transforming growth factor-beta secreted from CD4(+) T cells ameliorates antigen-induced eosinophilic inflammation - A novel high-dose tolerance in the trachea

The induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Tolerance induction in the in testine has been studied extensively and therapeutic applications to autoim munities are in progress, whereas tolerance in the respiratory tract is poo rly investigated. We examined the immunoregulatory mechanisms for evading e xaggerated inflammatory responses in the murine airway mucosa. Administrati on of an optimal dose of ovalbumin (OVA) to the trachea elicited eosinophil ic inflammation in the trachea of OVA/aluminum hydroxide-sensitized BALB/c mice, whereas higher doses were unable to do so. This failure paralleled th e downregulation of interleukin-4 production by mediastinal lymph node (LN) T cells. This high-dose tolerance was attributable to the mechanisms of ant igen (Ag)-specific suppression, because the adoptive transfer of CD4(+) LN T cells from the OVA-tolerant mice inhibited the OVA-specific, but not irre levant Ag KLH-specific, eosinophilic responses. The inhibitory effects were neutralized by the intratracheal administration of anti-transforming growt h factor (TGF)-beta, but not that of anti-interferon (IFN)-gamma, monoclona l antibodies, indicating that the high-dose tolerance was mediated by secre ted TGF-beta, but not by the dominance of transferred T helper (Th)1 cells over Th2 cells. The pivotal role of TGF-beta was reinforced by the finding that the LN cells from the OVA-tolerant mice produced TGF-beta in response to the in vitro Ag stimulation. These results demonstrate a novel regulator y mechanism in the airway: that TGF-beta secreted by T cells plays an impor tant role in the downmodulation of the immune responses to high doses of Ag which might otherwise induce deleterious inflammation in the airway mucosa l tissues.