Medicine and Health Sciences Commons^™

Ifn-Γ Causes Aplastic Anemia By Altering Hematopoietic Stem/Progenitor Cell Composition And Disrupting Lineage Differentiation, Fan Ching Lin, Megan Karwan, Bahara Saleh, Deborah L. Hodge, Tim Chan, Kimberly C. Boelte, Jonathan R. Keller, Howard A. Young

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Aplastic anemia (AA) is characterized by hypocellular marrow and peripheral pancytopenia. Because interferon gamma (IFN-γ) can be detected in peripheral blood mononuclear cells of AA patients, it has been hypothesized that autoreactive T lymphocytes may be involved in destroying the hematopoietic stem cells. We have observed AA-like symptoms in our IFN-γ adenylate-uridylate-rich element (ARE)-deleted (del) mice, which constitutively express a low level of IFN-γ under normal physiologic conditions. Because no T-cell autoimmunity was observed, we hypothesized that IFN-γ may be directly involved in the pathophysiology of AA. In these mice, we did not detect infiltration of T cells in bone …

Ifn-Gamma Au-Rich Element Removal Promotes Chronic Ifn-Gamma Expression And Autoimmunity In Mice, Deborah L. Hodge, Cyril Berthet, Vincenzo Coppola, Wolfgang Kastenmüller, Matthew D. Buschman, Paul M. Schaughency, Hidekazu Shirota, Anthony J. Scarzello, Jeff J. Subleski, Miriam R. Anver, John R. Ortaldo, Fanching Lin, Della A. Reynolds, Michael E. Sanford, Philipp Kaldis, Lino Tessarollo, Dennis M. Klinman, Howard A. Young

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We generated a mouse model with a 162 nt AU-rich element (ARE) region deletion in the 3' untranslated region (3'UTR) of the interferon-gamma (IFN-γ) gene that results in chronic circulating serum IFN-γ levels. Mice homozygous for the ARE deletion (ARE-Del) (-/-) present both serologic and cellular abnormalities typical of patients with systemic lupus erythematosus (SLE). ARE-Del(-/-) mice display increased numbers of pDCs in bone marrow and spleen. Addition of IFN-γ to Flt3-ligand (Flt3L) treated in vitro bone marrow cultures results in a 2-fold increase in pDCs with concurrent increases in IRF8 expression. Marginal zone B (MZB) cells and marginal zone …

Interferons: Success In Anti-Viral Immunotherapy, Fan Ching Lin, Howard A. Young

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The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens. These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface. Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs are considered as "standard of care" in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment …

Tumor Microenvironment-Based Feed-Forward Regulation Of Nos2 In Breast Cancer Progression, Julie L. Heinecke, Lisa A. Ridnour, Robert Y.S. Cheng, Christopher H. Switzer, Michael M. Lizardo, Chand Khanna, Sharon A. Glynn, S. Perwez Hussain, Howard A. Young, Stefan Ambs, David A. Wink

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Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance ourmechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER- and ER+ breast cancer cells and examined …

The Burden Of Influenza-Like Illness In The Us Workforce, Y. Tsai, F. Zhou, I. K. Kim

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Background -- The disease burden of influenza-like illnesses (ILIs) on the working population has been documented in the literature, but statistical evidence of ILI-related work absenteeism in the USA is limited due to data availability.

Aims -- To assess work absenteeism due to ILIs among privately insured employees in the USA in 2007–8 and 2008–9.

Methods -- We used the 2007–9 MarketScan® research databases. Full-time employees aged 18–64 years, with the ability to incur work absence and continuously enroled in the same insurance plan during each season were included. We identified ILI episodes using ICD-9 codes for influenza and …

Abrogation Of Tnfα Production During Cancer Immunotherapy Is Crucial For Suppressing Side Effects Due To The Systemic Expression Of Il-12, Bibiana Barrios, Natalia S. Baez, Della Reynolds, Pablo Iribarren, Hugo Cejas, Howard A. Young, Maria Cecilia Rodriguez-Galan

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For more than a decade, the cytokine interleukin-12 (IL-12) has been utilized, either alone or in combination with other drugs, as a treatment for cancer. The numerous anti-tumor properties of IL-12 still generate interest in the clinical use of this cytokine, even though it has demonstrated toxicity when administrated systemically. As an approach to overcome this toxicity, numerous laboratories have attempted to induce IL-12 expression at the site of the tumor. However for tumors that are difficult to remove surgically or for the treatment of disseminated metastases, systemic expression of this cytokine still remains as the most efficient method of …

Impaired Hcv Clearance In Hiv/Hcv Coinfected Subjects Treated With Pegifn And Rbv Due To Interference Of Ifn Signaling By Ifnαr2a, Yu Jin Lee, Xiaozhen Zhang, Estefania Vazquez, Gayathri Shivasabesan, Howard A. Young, Alison Murphy, Honghui Wang, Anthony F. Suffredini, Ulrich Siebenlist, Shyam Kottilil

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Enhanced endogenous interferon (IFN) stimulated gene (ISG) signature has been associated with nonresponsiveness to hepatitis C treatment using pegylated-IFNα (pegIFNα) and ribavirin (RBV) in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected patients. Using a proteomic approach, we identified high levels of IFNα receptor 2a (IFNαR2a) in the serum of null responders to pegIFNα/RBV. IFNαR2a inhibited antiviral activity of all formulations of IFNα in JFH/Huh7.5 cells. Furthermore, serum from null responders, but not from those who achieved sustained virologic response, suppressed IFN-signaling and ISG expression in IFNα-stimulated PBMCs of healthy donors in an IFNαR2a specific fashion. An IFNαR2a transgenic mice model …