ABSTRACT
Asthma is a heterogeneous disease characterized by airway inflammation and hyperreactivity. IL-17 receptor A (IL-17RA) is a shared receptor subunit required for activity of IL-17 family cytokines, including IL-17A and IL-25. IL-17A and IL-25 induce different proinflammatory responses, and concentrations are elevated in subjects with asthma. However, the individual contributions of IL-17A and IL-25 to disease pathogenesis are unclear. We explored proinflammatory activities of the IL-17 pathway in models of pulmonary inflammation and assessed its effects on contractility of human bronchial airway smooth muscle. In two mouse models, IL-17RA, IL-17RB, or IL-25 blockade reduced airway inflammation and airway hyperreactivity. Individually, IL-17A and IL-25 enhanced contractility of human bronchial smooth muscle induced by methacholine or carbachol. IL-17A had more pronounced effects on methacholine-induced contractility in bronchial rings from donors with asthma compared with donors without asthma. Blocking the IL-17 pathway via IL-17RA may be a useful therapy for some patients with asthma by reducing pulmonary inflammation and airway hyperreactivity.
Subject(s)
Asthma/metabolism , Receptors, Interleukin-17/physiology , Animals , Asthma/immunology , Bronchi/immunology , Bronchi/pathology , Cells, Cultured , Gene Expression , Humans , Interleukin-17/physiology , Interleukins/physiology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Muscle Contraction , Myocytes, Smooth Muscle/immunology , Myocytes, Smooth Muscle/metabolism , Signal TransductionABSTRACT
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.
Subject(s)
Adenosine/pharmacology , Autoimmune Diseases/prevention & control , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Inflammation/prevention & control , Protein Kinase Inhibitors/pharmacology , Quinolines/pharmacology , Adenosine/chemistry , Adenosine/metabolism , Animals , Cells, Cultured , Class I Phosphatidylinositol 3-Kinases/chemistry , Class I Phosphatidylinositol 3-Kinases/metabolism , Crystallography, X-Ray , Disease Models, Animal , Drug Discovery , Female , Humans , Mice, Inbred BALB C , Mice, Transgenic , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Quinolines/chemistry , Quinolines/metabolism , Rats, Inbred Lew , Sf9 Cells , Structure-Activity RelationshipSubject(s)
Autoimmune Diseases/enzymology , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Inflammation/enzymology , Phosphoinositide-3 Kinase Inhibitors , Animals , Autoimmune Diseases/drug therapy , B-Lymphocytes/enzymology , Class Ia Phosphatidylinositol 3-Kinase/chemistry , Class Ib Phosphatidylinositol 3-Kinase/chemistry , Humans , Inflammation/drug therapy , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Targeted Therapy , Neutrophils/enzymology , Protein Conformation , T-Lymphocytes/enzymologyABSTRACT
The ICOS (Inducible T cell Co-Stimulator)/B7RP-1 (B7-related protein 1) interaction is critical for the proper activation of a T lymphocyte. In this manuscript we describe a systematic in vivo approach to determine the level of blockade required to impair the generation of a T cell-dependent antibody response. We have developed an overall strategy for correlating drug exposure, target saturation, and efficacy in a biological response that can be generalized for most protein therapeutics. Using this strategy, we determined that low levels of B7RP-1 blockade are still sufficient to inhibit the immune response. These data suggest that contact between the T cell and the antigen-presenting cell during antigen presentation is much more sensitive to inhibition than previously believed and that ICOS/B7RP-1 blockade may be efficacious in the treatment of autoimmune diseases.
Subject(s)
B7-1 Antigen/pharmacology , Immune System Phenomena/drug effects , Aluminum Hydroxide/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antigen-Presenting Cells/immunology , Antigens, CD19/metabolism , B-Lymphocytes/metabolism , B7-1 Antigen/genetics , Binding Sites , CD3 Complex/metabolism , Cytokines/blood , Dose-Response Relationship, Drug , Female , Fluorescein-5-isothiocyanate/metabolism , Fluorescent Dyes/metabolism , Hemocyanins/immunology , Inducible T-Cell Co-Stimulator Ligand , Mice , Mice, Inbred BALB C , Models, Immunological , Protein Binding , Recombinant Fusion Proteins/pharmacology , T-Lymphocytes/metabolism , Temperature , Time FactorsABSTRACT
Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (T(FH) cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of T(FH) cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F(1) mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in T(FH) cells and GC B cells as well as an overall decrease in the frequency of ICOS(+) T cells. Coculture experiments of Ag-primed B cells with CXCR5(+) or CXCR5(-) T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the T(FH) cell pool is an important mechanism by which ICOS regulates Ab production.
