Am. J. Respir. Cell Mol. Biol., Volume 21, Number 2, August, 1999 268-274

Transforming Growth Factor- Secreted from CD4⁺ T Cells Ameliorates Antigen-Induced Eosinophilic Inflammation
A Novel High-Dose Tolerance in the Trachea

Kanna Haneda, Kunio Sano, Gen Tamura, Hidekazu Shirota, Yuichi Ohkawara, Takehito Sato, Sonoko Habu, and Kunio Shirato

First Department of Internal Medicine, Tohoku University School of Medicine, Sendai; and Department of Immunology, Tokai University School of Medicine, Isehara, Japan

The induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Tolerance induction in the intestine has been studied extensively and therapeutic applications to autoimmunities are in progress, whereas tolerance in the respiratory tract is poorly investigated. We examined the immunoregulatory mechanisms for evading exaggerated inflammatory responses in the murine airway mucosa. Administration of an optimal dose of ovalbumin (OVA) to the trachea elicited eosinophilic inflammation in the trachea of OVA/aluminum hydroxide-sensitized BALB/c mice, whereas higher doses were unable to do so. This failure paralleled the downregulation of interleukin-4 production by mediastinal lymph node (LN) T cells. This high-dose tolerance was attributable to the mechanisms of antigen (Ag)-specific suppression, because the adoptive transfer of CD4⁺ LN T cells from the OVA-tolerant mice inhibited the OVA-specific, but not irrelevant Ag KLH-specific, eosinophilic responses. The inhibitory effects were neutralized by the intratracheal administration of anti-transforming growth factor (TGF)-, but not that of anti-interferon (IFN)-, monoclonal antibodies, indicating that the high-dose tolerance was mediated by secreted TGF-, but not by the dominance of transferred T helper (Th)1 cells over Th2 cells. The pivotal role of TGF- was reinforced by the finding that the LN cells from the OVA-tolerant mice produced TGF- in response to the in vitro Ag stimulation. These results demonstrate a novel regulatory mechanism in the airway: that TGF- secreted by T cells plays an important role in the downmodulation of the immune responses to high doses of Ag which might otherwise induce deleterious inflammation in the airway mucosal tissues.

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