Orally administered TGF-β is biologically active in the intestinal mucosa and enhances oral tolerance

• Published in: Journal of allergy and clinical immunology 2007-10, Vol.120 (4), p.916-923
• Main Authors: Ando, Takashi, MD, PhD, Hatsushika, Kyosuke, MD, Wako, Masanori, MD, PhD, Ohba, Tetsuro, MD, Koyama, Kensuke, MD, Ohnuma, Yuko, Katoh, Ryohei, MD, PhD, Ogawa, Hideoki, MD, PhD, Okumura, Ko, MD, PhD, Luo, Jian, MD, PhD, Wyss-Coray, Tony, PhD, Nakao, Atsuhito, MD, PhD
• Format: Article
• Language: English
• Subjects: Administration, Oral; Allergic diseases; Allergy and Immunology; Animals; Biological and medical sciences; Digestive allergic diseases; Female; food allergy; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immune Tolerance - drug effects; Immunopathology; intestinal mucosa; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Transgenic; oral tolerance; Ovalbumin - immunology; Phosphorylation; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Smad; Smad2 Protein - metabolism; Smad7 Protein - genetics; TGF-β; Transforming Growth Factor beta - administration & dosage
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2007.05.023

Background Epidemiologic studies suggest that 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 We sought 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 means of in vivo imaging with transgenic mice expressing a Smad-responsive reporter construct (SBE-luc mice), by means of immunohistochemical staining with anti-phosphorylated Smad2 antibody, and by means of 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 means of high-dose ovalbumin (OVA) feeding. Results The oral administration of TGF-β increased Smad-responsive reporter activity in the intestines of SBE-luc mice and induced Smad2 phosphorylation and TGF-β and Smad7 mRNA expression in the intestines of BALB/c mice. Serum TGF-β levels were also increased after oral administration of TGF-β. BALB/c mice treated orally with OVA and TGF-β showed augmented reduction of OVA-specific IgE and IgG1 antibodies, T-cell reactivity, and immediate-type skin reactions when compared with the mice treated orally with OVA alone. Conclusions Orally administered TGF-β retains sufficient biologic activity in intestinal mucosa and enhances oral tolerance. Clinical implications Oral administration of TGF-β might become a potential strategy to prevent allergic diseases, such as food allergy.