ABSTRACT
BACKGROUND: Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. METHODS: To analyze the therapeutic effects of sGARP, adult NOD/Scidγc(-/-) (NSG) mice received peripheral blood mononuclear cells (PBMC) derived from allergic patients with sensitization against birch allergen. Subsequently, allergic inflammation was induced in the presence of Treg alone or in combination with sGARP. RESULTS: In comparison with mice that received Treg alone, additional treatment with sGARP reduced airway hyperresponsiveness (AHR), influx of neutrophils and macrophages into the bronchoalveolar lavage (BAL), and human CD45(+) cells in the lungs. Furthermore, the numbers of mucus-producing goblet cells and inflammatory cell infiltrates were reduced. To elucidate whether the mechanism of action of sGARP involves the TGF-ß receptor pathway, mice additionally received anti-TGF-ß receptor II (TGF-ßRII) antibodies. Blocking the signaling of TGF-ß through TGF-ßRII abrogated the anti-inflammatory effects of sGARP, confirming its essential role in inhibiting the allergic inflammation. CONCLUSION: Induction of peripheral tolerance via sGARP is a promising potential approach to treat allergic airway diseases.
Subject(s)
Inflammation/etiology , Inflammation/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Respiratory Hypersensitivity/etiology , Respiratory Hypersensitivity/metabolism , Adult , Allergens/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Disease Models, Animal , Female , Humans , Immune Tolerance , Immunoglobulin E/blood , Immunoglobulin E/immunology , Inflammation/pathology , Lung/immunology , Lung/metabolism , Lung/pathology , Male , Mice , Middle Aged , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/metabolism , Respiratory Hypersensitivity/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolismABSTRACT
Neurofibromatosis is a multifaceted progressive genetic disorder with no known cure. Although early identification is desirable, it is seldom possible since signs and symptoms may take years to manifest sufficiently to confirm a diagnosis. Careful monitoring by a consistent health care provider improves the chances of patient and family receiving appropriate information and care.
