The Role of Transforming Growth Factor Beta (TGFbeta) in Promoting Allergic Inflammation

National Institute Of Allergy And Infectious Diseases

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Abstract

Food allergy and other allergic conditions have become increasingly common both in the United States and in other developed countries around the world. While both genetic and environmental factors likely contribute to the development of food allergy and other allergic conditions, the complex interaction between these variables has frustrated efforts to elucidate pathogenesis and develop mechanism-targeted therapies. We have demonstrated that patients with Loeys-Dietz Syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding the receptor for TGF, TGFBRI and TGFBR2, are at significantly increased risk of developing nearly all forms of allergic disease, including food allergy, asthma, eosinophilic esophagitis (EoE), eczema and allergic rhinitis. Mice harboring a knock-in mutation (TgfbrIM318R/+) known to cause severe disease in humans also develop an allergic phenotype, including the spontaneous development of EoE with 100% penetrance. To examine the role of the hematopoietic and nonhematopoietic compartments in the development of EoE, we've developed a novel technique to generate neonatal bone marrow chimeric mice. While established protocols exist to transplant hematopoietic stem cells into irradiated or chemically myeloablated adult mice or unirradiated immunodeficient mice, this protocol allows efficient reconstitution of immune-replete neonatal mice. This technique is instrumental in studying allergic phenotypes that develop during the neonatal period and whose pathogenesis involves interactions between hematopoietic and nonhematopoietic compartments.