315 Exogenous PGI2 Protection Against Respiratory Syncytial. Virus (RSV)-Induced IL-13-Producing Th2 Cells and ILC2. Melissa T. Harintho, BS1, Shinji Toki, ...
Exogenous PGI2 Protection Against Respiratory Syncytial Virus (RSV)-Induced IL-13-Producing Th2 Cells and ILC2 Melissa T. Harintho, BS1, Shinji Toki, PhD2, Kasia Goleniewska2, R. Stokes Peebles, Jr, MD, FAAAAI3; 1Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 2Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 3Vanderbilt University School of Medicine, Nashville, TN. RATIONALE: RSV is the leading cause of hospitalization in infants. Severe RSV infection is also a risk factor for the subsequent development of asthma. During RSV infection, IL-13 mediates mucus production, which directly contributes to airway obstruction and respiratory failure. Our laboratory previously showed that endogenous prostaglandin (PG) I2 reduced RSV-induced illness in mice. To pave the way for a clinical effectiveness study using PGI2 for the treatment of RSV infection, we performed preclinical studies to determine how exogenous PGI2 impacts RSVinduced illness and determine the mechanisms by which exogenous PGI2 modulates host antiviral immunity. METHODS: 8 week old BALB/c WT mice were infected with 1x106 PFU of RSV clinical isolate strain 00/12-35. Beginning 24 hours after infection, mice were treated with the exogenous PGI2 analog cicaprost (2 mg/50 ml) or PBS (vehicle, 50 ml) every 12 hours. Lungs were harvested 4 and 6 days after infection. IL-13, IL-10, and IFN-g levels were evaluated by ELISA. IL-13+Th2 cells and group 2 innate lymphoid cells (ILC2) were identified by flow cytometry. RESULTS: Compared to vehicle-treated mice, cicaprost-treated mice had significantly decreased lung IL-13 and IL-13+Th2 cells 4 days after RSV infection. Lung IL-10 and IFN-g were significantly increased, while ILC2s were significantly decreased 6 days following RSV infection in cicaprosttreated mice compared to vehicle-treated mice. CONCLUSIONS: These data suggest that exogenous PGI2 protects against RSV 00/12-35-induced IL-13-producing Th2 cells and ILC2.
The Use of Radiolabelled 18-F-2-Deoxy-2-Fluro-Glucose (18FDG) in Combined Positron Emission Tomography-Computed Tomography (PET-CT) to Evaluate Infection: Lessons Learned from a Case Series of 23 Patients with Chronic Granulomatous Disease (CGD) Amanda K. Rudman Spergel, MD1, Clara C. Chen, MD2, Cheryl Ann Beegle, JD, CRA2, Patricia Littel, RN, BSN1, Mary Garofalo, RN, BSN1, Sandra Anaya-O’Brien, RN, MSN1, Martha Marquesen, CRNP1, Ulas Bagci, PhD3, Daniel J. Mollura, MD3, John I. Gallin, MD1, Harry L. Malech, MD1; 1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 2Nuclear Medicine Section, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, 3Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD. RATIONALE: Use of 18-FDG in PET-CT is gaining acceptance in diagnosis and monitoring of infection and inflammatory disorders. We describe lessons learned in patients with CGD. METHODS: 23 CGD patients underwent 18-FDG PET-CT imaging. 10 patients were imaged as part of a dedicated infection work-up, while 13 patients were evaluated during general diagnostic assessment. RESULTS: First, known sites of active bacterial or fungal infection are always associated with intense 18-FDG uptake, but are often surprisingly heterogeneous in comparison to CT. Second, stable pulmonary lesions that are residual sequelae of long resolved infections have 18-FDG uptake on par with background. Third, CGD lymphadenopathy observed by CT, but unrelated to infection, lack intense 18-FDG uptake. Fourth, focal uptake in the musculoskeletal system can be due to recent trauma, so clinical correlation should be ascertained before assuming an infectious process. Fifth, clinical resolution of infection is closely associated with diminished 18-FDG uptake. CONCLUSIONS: 18-FDG PET-CT can define areas of infection, and studies are warranted to determine whether biopsy of areas of highest
J ALLERGY CLIN IMMUNOL FEBRUARY 2015
intensity may result in improved yield. CGD lymphadenopathy or granuloma unrelated to infection is surprisingly lacking in significantly increased 18-FDG uptake. Our observations suggest that it may be possible to use 18-FDG PET-CT to identify the scope and intensity of infection in patients with CGD and, in complex multifocal infection, may better assess overall resolution and response to therapy than CT alone.
(1) Immunopharmacological Characterization of Potent, Selective and Orally Available RORgt Inhibitors for Treatment of Autoimmune Diseases Junya Masuda, Takashi Takeuchi, Chinatsu Tomizawa, Atsuko Kawaji, Toshimichi Asakura, Shunsuke Shimada, Takaaki Negishi, Yutaka Kato, Kazunari Nakao, Shoji Furusako; Discovery Research, Mochida Pharmaceutical Co., LTD., Gotemba, Shizuoka, Japan. RATIONALE: Th17 cells, functionally regulated by the transcription factor RORgt, play key roles in the pathogenesis of autoimmune diseases. Here we report the immunopharmacological characterization of our novel RORgt inhibitors in comparison with a JAK inhibitor. METHODS: The effects on Th17 differentiation and Th1/Th17 cytokine production were evaluated using human peripheral mononuclear blood cells or mouse splenocytes stimulated with anti-CD3/anti-CD28 antibodies. Specificity and safety profiles were assessed by BioMAP T cell autoimmune panel that models immunosuppression, anti-inflammatory action, tissue remodeling, Th1/Th2/Th17 skewing, and cell cytotoxicity in human primary cells. In vivo pharmacological effect was tested in a mouse experimental autoimmune encephalomyelitis (EAE) model. RESULTS: The lead compound MG2905 showed potent inhibitory effects on IL-17A production in human and mouse systems (IC50 values were < 5 nM and < 30 nM, respectively) without affecting IFN-g production. The IC90 value in human was about < 200 nM in the presence of 50% human serum. In contrast, a JAK inhibitor Tofacitinib enhanced IL-17A production in a bell-shaped fashion although it inhibited IFN-g production in a dose-dependent manner. IL-17-specific profile of MG2905 was also supported by human T cell autoimmune panel, where other immunosuppressant drugs e.g. Tofacitinib broadly inhibited immune responses. In mouse EAE model, oral administration of MG2905 resulted in suppression of clinical score. CONCLUSIONS: We developed potent, selective, and orally-available RORgt inhibitors possessing clean Th17-specific immunopharmacologic profile which should be useful for the treatment of autoimmune diseases.