Oral TGF-p: mechanisms of action and application to allergic disease

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Background: Epidemiological studies suggest that transforming growth factor-β (TGF-β) in breast milk provides protection against allergic disease during infancy. However, it is unclear whether orally administered TGF-β, such as TGF-β in human milk, retains and exerts its activity in the intestinal mucosa and can affect immune response (tolerance) to dietary antigens.Objective: To determine whether orally administered TGF-β is biologically active in intestinal mucosa and affects oral tolerance.Methods: Activity of orally administered TGF-β in the intestinal mucosa was evaluated by in vivo imaging using transgenic mice expressing a Smad-responsive reporter construct (SBE-luc mice), by immunohistochemical staining with anti-phosphorylated Smad2 antibody, and by real-time RT-PCR analysis of TGF-β and Smad7 mRNA expression. The effects of orally administered TGF-β on oral tolerance induction were assessed in mice tolerized by high-dose ovalbumin (OVA) feeding.Results: The oral administration of TGF-β increased Smad-responsive reporter activity in the intestine of SBE-luc mice and induced Smad2 phosphorylation and TGF-β and Smad7 mRNA expression in the intestine of BALB/c mice. Serum TGF-6 levels were also increased after oral administration of TGF-β. BALB/c mice treated orally with OVA and TGF-I3 showed augmented reduction of OVA-specific IgE and IgG1 antibodies, T cell reactivity, and immediate-type skin reaction when compared with the mice treated orally with OVA alone.Conclusions: Orally administered TGF-β retains sufficient biological activity in intestinal mucosa and enhances oral tolerance.Clinical implications: Oral administration of TGF-β might become a potential strategy to prevent allergic disease such as food allergy.