![]() ![]() ![]() Although three distinct transmembrane glycoprotein subunits contribute to the formation of the "definitive" high affinity IL-2 receptor, various combinations of receptor subunits are known to occur. The biological activities of IL-2 are mediated through its binding to a multisubunit cellular receptor. Interleukin 2 (IL-2) is a lymphokine synthesized and secreted primarily by T-helper lymphocytes that have been activated by stimulation with certain mitogens or by interaction of the T-cell receptor complex with an antigen/MHC complex on the surfaces of antigen-presenting cells. Recently, an anti-IFNγ antibody (Fontolizumab) has been demonstrated to be of a clinical benefit in patients suffering from Crohn's disease. These observations suggest that IFN-γ antagonist may have therapeutic application in autoimmune diseases, chronic inflammation, and allograft rejection. Additionally, administration of IFN-γ can promote the development of reactive gliosis in the central nervous system (CNS) of adult mice and aggravate the course of multiple sclerosis in humans. IFN-γ-mediates pancreatic beta-cell death and the subsequent development of immune-mediated diabetes and accelerates the development of lupus-like disease and nephritis in NZW × NZB- after treatment of F1 mice, whereas antibodies to IFN-γ can block or delay the progression of the disease. IFN-γ neutralization inhibits the lethal effect of endotoxin in an animal model of septic shock, as well as the rejection of tumor, skin, and heart allografts. Several pathological effects have been ascribed to IFN-γ in animal models and in humans. IFNGR1 has an extracellular portion of 228 residues, that also occurs in soluble form and can function as an endogenous IFN-γ inhibitor. The receptor comprises two subunits (IFNGR1 and IFNGR2). The activities of IFN-γ are initiated following association of the cytokine with a membrane-bound receptor (IFNGR) present on many cell types. ![]() Interferon gamma (IFN-γ), produced by activated T and NK cells, macrophages and dendritic cells, has important immunomodulatory and inflammatory actions. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases. TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. It was then solubilized with strong denaturant and finally refolded by gel filtration. The protein was partially purified by pelleting and washing. The chimeric protein was expressed at high level as inclusion bodies. coli (W3110 strain) was transformed with this vector. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. coli, purified and evaluated for its in vitro biological activities. ResultsĪ chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. ![]() TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |