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Articles 1 - 30 of 33
Full-Text Articles in Medicine and Health Sciences
Meeting Overview: Interferon Lambda - Disease Impact And Therapeutic Potential, Thomas R. O'Brien, Howard A. Young, Raymond P. Donnelly, Ludmila Prokunina-Olsson
Meeting Overview: Interferon Lambda - Disease Impact And Therapeutic Potential, Thomas R. O'Brien, Howard A. Young, Raymond P. Donnelly, Ludmila Prokunina-Olsson
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A meeting entitled, "Interferon Lambda: Disease Impact and Translational Potential," was held on the campus of the National Institutes of Health in Bethesda, Maryland, on October 25-26, 2018. To our knowledge, this was the first meeting that focused exclusively on interferon lambda (IFN-λ). The meeting's purpose was to enhance interdisciplinary communication and promote new collaborations. The gathering brought together an international group of scientists from a wide range of disciplines. Sessions included: IFN-λ Biology, Therapy and Genetic Variation; IFN-λ and Hepatitis C Virus Infection; IFN-λ in Other Infections; and IFN-λ - Hepatic Fibrosis and Cancer. The next meeting on IFN-λ …
Durvalumab In Combination With Olaparib In Patients With Relapsed Sclc: Results From A Phase Ii Study, Anish Thomas, Rasa Vilimas, Christopher Trindade, Rebecca Erwin-Cohen, Nitin Roper, Liqiang Xi, Venkatesh Krishnasamy, Elliot Levy, Andy Mammen, Samantha Nichols, Yuanbin Chen, Vamsidhar Velcheti, Faye Yin, Eva Szabo, Yves Pommier, Seth M. Steinberg, Jane B. Trepel, Mark Raffeld, Howard A. Young, Javed Khan, Stephen Hewitt, Jung Min Lee
Durvalumab In Combination With Olaparib In Patients With Relapsed Sclc: Results From A Phase Ii Study, Anish Thomas, Rasa Vilimas, Christopher Trindade, Rebecca Erwin-Cohen, Nitin Roper, Liqiang Xi, Venkatesh Krishnasamy, Elliot Levy, Andy Mammen, Samantha Nichols, Yuanbin Chen, Vamsidhar Velcheti, Faye Yin, Eva Szabo, Yves Pommier, Seth M. Steinberg, Jane B. Trepel, Mark Raffeld, Howard A. Young, Javed Khan, Stephen Hewitt, Jung Min Lee
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Purpose: Despite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade. Methods: A single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells …
Ion Gresser 1928-2019, Jan Vilcek, Howard A. Young
Ion Gresser 1928-2019, Jan Vilcek, Howard A. Young
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Ion Gresser, a virologist who transformed understanding of the roles of interferons, may be best remembered for showing that in mice, interferon-α (IFN-α) can produce acute and chronic disease. At the time Gresser began these studies, interferon was considered to be a selective antiviral substance, harmless to uninfected cells and organisms, and there was no indication that cytokines would play a role in pathogenesis. That belief was shattered with the 1975 Nature publication with the simple title “Lethality of interferon preparations for newborn mice.” Gresser subsequently demonstrated that antibodies to IFN-α can protect young mice from death caused by infection …
Ifn-Γ: A Cytokine At The Right Time, Is In The Right Place, J. Daniel Burke, Howard A. Young
Ifn-Γ: A Cytokine At The Right Time, Is In The Right Place, J. Daniel Burke, Howard A. Young
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Interferon gamma has long been studied as a critical mediator of tumor immunity. In recent years, the complexity of cellular interactions that take place in the tumor microenvironment has become better appreciated in the context of immunotherapy. While checkpoint inhibitors have dramatically improved remission rates in cancer treatment, IFN-Γ and related effectors continue to be identified as strong predictors of treatment success. In this review, we provide an overview of the multiple immunosuppressive barriers that IFN-Γ has to overcome to eliminate tumors, and potential avenues for modulating the immune response in favor of tumor rejection.
Report On The 2018 Cancer, Autoimmunity, And Immunology Conference, Colleen S. Curran, Connie L. Sommers, Howard A. Young, Katarzyna Bourcier, Marie Mancini, Elad Sharon
Report On The 2018 Cancer, Autoimmunity, And Immunology Conference, Colleen S. Curran, Connie L. Sommers, Howard A. Young, Katarzyna Bourcier, Marie Mancini, Elad Sharon
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With the increased use of cancer immunotherapy, a number of immune-related adverse events (irAEs) are being identified. These irAEs can be compared with known autoimmune disorders in similar tissues, with important similarities and differences. Understanding the etiology of irAEs may bring to light concepts applicable to immune responses in cancer, autoimmunity, and infectious disease. This immunobiology is especially relevant to cancer patients with preexisting allogeneic transplants or autoimmune disease who are undergoing cancer immunotherapy. To address these facets of cancer immunotherapy, academic leaders from these various disciplines discussed current irAE basic and clinical research, irAE diagnosis and management, and the …
Critical Role Of Post-Transcriptional Regulation For Ifn-Γ In Tumor-Infiltrating T Cells, Fiamma Salerno, Aurelie Guislain, Julian J. Freen-Van Heeren, Benoit P. Nicolet, Howard A. Young, Monika C. Wolkers
Critical Role Of Post-Transcriptional Regulation For Ifn-Γ In Tumor-Infiltrating T Cells, Fiamma Salerno, Aurelie Guislain, Julian J. Freen-Van Heeren, Benoit P. Nicolet, Howard A. Young, Monika C. Wolkers
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Protective T cell responses against tumors require the production of Interferon gamma (IFN-γ). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-γ and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products. Here we show that although TILs express substantial levels of Ifng mRNA, post-transcriptional mechanisms impede the production of IFN-γ protein due to loss of mRNA stability. CD28 triggering, but not PD1 blocking antibodies, effectively restores the stability of Ifng mRNA. Intriguingly, TILs devoid of AU-rich elements within the 3ʹuntranslated region maintain stabilized …
Thymic Expression Of Il-4 And Il-15 After Systemic Inflammatory Or Infectious Th1 Disease Processes Induce The Acquisition Of"Innate" Characteristics During Cd8 + T Cell Development, Natalia S. Baez, Fabio Cerbán, Constanza Savid-Frontera, Deborah L. Hodge, Jimena Tosello, Eva Acosta-Rodriguez, Laura Almada, Adriana Gruppi, Maria Estefania Viano, Howard A. Young, Maria Cecilia Rodriguez-Galan
Thymic Expression Of Il-4 And Il-15 After Systemic Inflammatory Or Infectious Th1 Disease Processes Induce The Acquisition Of"Innate" Characteristics During Cd8 + T Cell Development, Natalia S. Baez, Fabio Cerbán, Constanza Savid-Frontera, Deborah L. Hodge, Jimena Tosello, Eva Acosta-Rodriguez, Laura Almada, Adriana Gruppi, Maria Estefania Viano, Howard A. Young, Maria Cecilia Rodriguez-Galan
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Innate CD8 + T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8 + T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, …
Partners In Crime: Fledgling Tumors Hijack Inflammation, Balamurugan Kuppusamy, Howard A. Young
Partners In Crime: Fledgling Tumors Hijack Inflammation, Balamurugan Kuppusamy, Howard A. Young
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While inflammation is a normal physiological response after tissue injury, the chemicals/mediators that are released by the damaged tissue can be toxic to the cells. This underlying inflammation increases the likelihood of cellular DNA damage and aberrant cell growth (Kiraly and others 2015). In this scenario, inflammation functions as a ‘‘behind-curtain factor’’ for many disorders. Cancer has long been known to be closely tethered to inflammation. Widespread evidence shows that inflammatory diseases such as colitis, pancreatitis, and hepatitis make their respective organs highly susceptible to eventual cancer development (Shalapour and Karin 2015). However, other studies have shown that in due …
Translational Repression Of Pre-Formed Cytokine-Encoding Mrna Prevents Chronic Activation Of Memory T Cells, Fiamma Salerno, Sander Engels, Maartje Van Den Biggelaar, Floris P.J. Van Alphen, Aurelie Guislain, Wanqi Zhao, Deborah L. Hodge, Sarah E. Bell, Jan Paul Medema, Marieke Von Lindern, Martin Turner, Howard A. Young, Monika C. Wolkers
Translational Repression Of Pre-Formed Cytokine-Encoding Mrna Prevents Chronic Activation Of Memory T Cells, Fiamma Salerno, Sander Engels, Maartje Van Den Biggelaar, Floris P.J. Van Alphen, Aurelie Guislain, Wanqi Zhao, Deborah L. Hodge, Sarah E. Bell, Jan Paul Medema, Marieke Von Lindern, Martin Turner, Howard A. Young, Monika C. Wolkers
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Memory T cells are critical for the immune response to recurring infections. Their instantaneous reactivity to pathogens is empowered by the persistent expression of cytokine-encoding mRNAs. How the translation of proteins from pre-formed cytokine-encoding mRNAs is prevented in the absence of infection has remained unclear. Here we found that protein production in memory T cells was blocked via a 3′ untranslated region (3′ UTR)-mediated process. Germline deletion of AU-rich elements (AREs) in the Ifng-3′ UTR led to chronic cytokine production in memory T cells. This aberrant protein production did not result from increased expression and/or half-life of the mRNA. Instead, …
Interferon-Gamma Impairs Maintenance And Alters Hematopoietic Support Of Bone Marrow Mesenchymal Stromal Cells, Marieke Goedhart, Anne S. Cornelissen, Carlijn Kuijk, Sulima Geerman, Marion Kleijer, Jaap D. Van Buul, Stephan Huveneers, Marc H.G.P. Raaijmakers, Howard A. Young, Monika C. Wolkers, Carlijn Voermans, Martijn A. Nolte
Interferon-Gamma Impairs Maintenance And Alters Hematopoietic Support Of Bone Marrow Mesenchymal Stromal Cells, Marieke Goedhart, Anne S. Cornelissen, Carlijn Kuijk, Sulima Geerman, Marion Kleijer, Jaap D. Van Buul, Stephan Huveneers, Marc H.G.P. Raaijmakers, Howard A. Young, Monika C. Wolkers, Carlijn Voermans, Martijn A. Nolte
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Bone marrow (BM) mesenchymal stromal cells (MSCs) provide microenvironmental support to hematopoietic stem and progenitor cells (HSPCs). Culture-expanded MSCs are interesting candidates for cellular therapies due to their immunosuppressive and regenerative potential which can be further enhanced by pretreatment with interferon-gamma (IFN-γ). However, it remains unknown whether IFN-γ can also influence hematopoietic support by BM-MSCs. In this study, we elucidate the impact of IFN-γ on the hematopoietic support of BM-MSCs. We found that IFN-γ increases expression of interleukin (IL)-6 and stem cell factor by human BM-MSCs. IFN-γ-treated BM-MSCs drive HSPCs toward myeloid commitment in vitro, but impair subsequent differentiation of …
The Interplay Of Type I And Type Ii Interferons In Murine Autoimmune Cholangitis As A Basis For Sex-Biased Autoimmunity, Heekyong R. Bae, Deborah L. Hodge, Guo Xiang Yang, Patrick S.C. Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M E. Gershwin, Howard A. Young
The Interplay Of Type I And Type Ii Interferons In Murine Autoimmune Cholangitis As A Basis For Sex-Biased Autoimmunity, Heekyong R. Bae, Deborah L. Hodge, Guo Xiang Yang, Patrick S.C. Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M E. Gershwin, Howard A. Young
Public Health Resources
We have reported on a murine model of autoimmune cholangitis, generated by altering the AU-rich element (ARE) by deletion of the interferon gamma (IFN-γ) 3' untranslated region (coined ARE-Del−/−), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the sex bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del−/− …
Therapeutic And Immunological Interventions In Primary Biliary Cholangitis: From Mouse Models To Humans, Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin
Therapeutic And Immunological Interventions In Primary Biliary Cholangitis: From Mouse Models To Humans, Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin
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Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that predominantly affects women in their fifth and sixth decades. The diagnostic hallmarks of PBC are detection of anti-mitochondrial antibodies (AMAs) and chronic non-suppurative destructive cholangitis (CNSDC) of small- and medium-sized intrahepatic bile ducts in liver histological examination [1, 2]. A significant amount of data suggests that immunological activity against small biliary epithelial cells (BECs), found histologically as portal inflammation, leads to clinical disease. In PBC, as with other autoimmune diseases, both genetic and environmental factors contribute to the development of pathology [3–8]. The first-line therapy of PBC is ursodeoxycholic …
Current Prospects Of Type Ii Interferon Γ Signaling & Autoimmunity, Daniel S. Green, Howard A. Young, Julio C. Valencia
Current Prospects Of Type Ii Interferon Γ Signaling & Autoimmunity, Daniel S. Green, Howard A. Young, Julio C. Valencia
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Interferon γ (IFNγ) is a pleiotropic protein secreted by immune cells. IFNγ signals through the IFNγ receptor, a protein complex that mediates downstream signaling events. Studies into IFNγ signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFNγ is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFNγ signaling biology and the functional roles of IFNγ in the autoimmune response.
Rapid And Rigorous Il-17a Production By A Distinct Subpopulation Of Effector Memory T Lymphocytes Constitutes A Novel Mechanism Of Toxic Shock Syndrome Immunopathology, Peter A. Szabo, Ankur Goswami, Delfina M. Mazzuca, Kyoungok Kim, David B. O'Gorman, David A. Hess, Ian D. Welch, Howard A. Young, Bhagirath Singh, John K. Mccormick, S. M.Mansour Haeryfar
Rapid And Rigorous Il-17a Production By A Distinct Subpopulation Of Effector Memory T Lymphocytes Constitutes A Novel Mechanism Of Toxic Shock Syndrome Immunopathology, Peter A. Szabo, Ankur Goswami, Delfina M. Mazzuca, Kyoungok Kim, David B. O'Gorman, David A. Hess, Ian D. Welch, Howard A. Young, Bhagirath Singh, John K. Mccormick, S. M.Mansour Haeryfar
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Toxic shock syndrome (TSS) is caused by staphylococcal and streptococcal superantigens (SAgs) that provoke a swift hyperinflammatory response typified by a cytokine storm. The precipitous decline in the host's clinical status and the lack of targeted therapies for TSS emphasize the need to identify key players of the storm's initial wave. Using a humanized mouse model of TSS and human cells, we herein demonstrate that SAgs elicit in vitro and in vivo IL-17A responses within hours. SAg-triggered human IL-17A production was characterized by remarkably high mRNA stability for this cytokine. A distinct subpopulation of CD4+ effector memory T (TEM) cells …
Th1 Differentiation Drives The Accumulation Of Intravascular, Non-Protective Cd4 T Cells During Tuberculosis, Michelle A. Sallin, Shunsuke Sakai, Keith D. Kauffman, Howard A. Young, Jinfang Zhu, Daniel L. Barber
Th1 Differentiation Drives The Accumulation Of Intravascular, Non-Protective Cd4 T Cells During Tuberculosis, Michelle A. Sallin, Shunsuke Sakai, Keith D. Kauffman, Howard A. Young, Jinfang Zhu, Daniel L. Barber
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Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of …
Toward Solving The Etiological Mystery Of Primary Biliary Cholangitis, Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin
Toward Solving The Etiological Mystery Of Primary Biliary Cholangitis, Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin
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Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti-mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome-wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced …
Regulation Of Ifn-Γ Expression, John Fenimore, Howard A. Young
Regulation Of Ifn-Γ Expression, John Fenimore, Howard A. Young
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Interferon gamma, referred to here as IFN- γ, is a major component in immunological cell signaling and is a critical regulatory protein for overall immune system function. First discovered in 1965 (Wheelock Science 149: (3681)310–311, 1965), IFN- γ is the only Type II interferon identified. Its expression is both positively and negatively controlled by different factors. In this chapter, we will review the transcriptional and post-transcriptional control of IFN-γ expression. In the transcriptional control part, the regular activators and suppressors are summarized, we will also focus on the epigenetic control, such as chromosome access, DNA methylation, and histone acetylation. The …
Chronic Expression Of Interferon-Gamma Leads To Murine Autoimmune Cholangitis With A Female Predominance, Heekyong R. Bae, Patrick S.C. Leung, Koichi Tsuneyama, Julio C. Valencia, Deborah L. Hodge, Seohyun Kim, Tim Back, Megan Karwan, Anand S. Merchant, Nobuyuki Baba, Dechun Feng, Ogyi Park, Bin Gao, Guo Xiang Yang, M. Eric Gershwin, Howard A. Young
Chronic Expression Of Interferon-Gamma Leads To Murine Autoimmune Cholangitis With A Female Predominance, Heekyong R. Bae, Patrick S.C. Leung, Koichi Tsuneyama, Julio C. Valencia, Deborah L. Hodge, Seohyun Kim, Tim Back, Megan Karwan, Anand S. Merchant, Nobuyuki Baba, Dechun Feng, Ogyi Park, Bin Gao, Guo Xiang Yang, M. Eric Gershwin, Howard A. Young
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In most autoimmune diseases the serologic hallmarks of disease precede clinical pathology by years. Therefore, the use of animal models in defining early disease events becomes critical. We took advantage of a “designer” mouse with dysregulation of interferon gamma (IFNγ) characterized by prolonged and chronic expression of IFNγ through deletion of the IFNγ 3′-untranslated region adenylate uridylate-rich element (ARE). The ARE-Del-/- mice develop primary biliary cholangitis (PBC) with a female predominance that mimics human PBC that is characterized by up-regulation of total bile acids, spontaneous production of anti-mitochondrial antibodies, and portal duct inflammation. Transfer of CD4 T cells from ARE-Del-/- …
Cd4 T Cell-Derived Ifn-Γ Plays A Minimal Role In Control Of Pulmonary Mycobacterium Tuberculosis Infection And Must Be Actively Repressed By Pd-1 To Prevent Lethal Disease, Shunsuke Sakai, Keith D. Kauffman, Michelle A. Sallin, Arlene H. Sharpe, Howard A. Young, Vitaly V. Ganusov, Daniel L. Barber
Cd4 T Cell-Derived Ifn-Γ Plays A Minimal Role In Control Of Pulmonary Mycobacterium Tuberculosis Infection And Must Be Actively Repressed By Pd-1 To Prevent Lethal Disease, Shunsuke Sakai, Keith D. Kauffman, Michelle A. Sallin, Arlene H. Sharpe, Howard A. Young, Vitaly V. Ganusov, Daniel L. Barber
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IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death …
Aging Converts Innate B1a Cells Into Potent Cd8+ T Cell Inducers, Catalina Lee-Chang, Monica Bodogai, Kanako Moritoh, Xin Chen, Robert Wersto, Ranjan Sen, Howard A. Young, Michael Croft, Luigi Ferrucci, Arya Biragyn
Aging Converts Innate B1a Cells Into Potent Cd8+ T Cell Inducers, Catalina Lee-Chang, Monica Bodogai, Kanako Moritoh, Xin Chen, Robert Wersto, Ranjan Sen, Howard A. Young, Michael Croft, Luigi Ferrucci, Arya Biragyn
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B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL+ MHC class-IHi CD86Hi B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN-gR1 on B1a cells to subsequently upregulate membrane TNF-α and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8+ T cells by …
Surface Display Of Glycosylated Tyrosinase Related Protein-2 (Trp-2) Tumour Antigen On Lactococcus Lactis, Jeevanathan Kalyanasundram, Suet Lin Chia, Adelene Ai Lian Song, Abdul Rahim Raha, Howard A. Young, Khatijah Yusoff
Surface Display Of Glycosylated Tyrosinase Related Protein-2 (Trp-2) Tumour Antigen On Lactococcus Lactis, Jeevanathan Kalyanasundram, Suet Lin Chia, Adelene Ai Lian Song, Abdul Rahim Raha, Howard A. Young, Khatijah Yusoff
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Background: The exploitation of the surface display system of food and commensal lactic acid bacteria (LAB) for bacterial, viral, or protozoan antigen delivery has received strong interest recently. The Generally Regarded as Safe (GRAS) status of the Lactococcus lactis coupled with a non-recombinant strategy of in-trans surface display, provide a safe platform for therapeutic drug and vaccine development. However, production of therapeutic proteins fused with cell-wall anchoring motifs is predominantly limited to prokaryotic expression systems. This presents a major disadvantage in the surface display system particularly when glycosylation has been recently identified to significantly enhance epitope presentation. In this study, …
Architecture Of High-Affinity Unnatural-Base Dna Aptamers Toward Pharmaceutical Applications, Ken Ichiro Matsunaga, Michiko Kimoto, Charlotte Hanson, Michael Sanford, Howard A. Young, Ichiro Hirao
Architecture Of High-Affinity Unnatural-Base Dna Aptamers Toward Pharmaceutical Applications, Ken Ichiro Matsunaga, Michiko Kimoto, Charlotte Hanson, Michael Sanford, Howard A. Young, Ichiro Hirao
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We present a remodeling method for high-affinity unnatural-base DNA aptamers to augment their thermal stability and nuclease resistance, for use as drug candidates targeting specific proteins. Introducing a unique mini-hairpin DNA provides robust stability to unnatural-base DNA aptamers generated by SELEX using genetic alphabet expansion, without reducing their high affinity. By this method, >80% of the remodeled DNA aptamer targeting interferon-γ (KD of 33 pM) survived in human serum at 37 °C after 3 days under our experimental conditions, and sustainably inhibited the biological activity of interferon-γ.
Impact Of Dietary Components On Nk And Treg Cell Function For Cancer Prevention, Young S. Kim, Thomas J. Sayers, Nancy H. Colburn, John A. Milner, Howard A. Young
Impact Of Dietary Components On Nk And Treg Cell Function For Cancer Prevention, Young S. Kim, Thomas J. Sayers, Nancy H. Colburn, John A. Milner, Howard A. Young
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An important characteristic of cancer is that the disease can overcome the surveillance of the immune system. A possible explanation for this resistance arises from the ability of tumor cells to block the tumoricidal activity of host immune cells such as natural killer (NK) cells by inducing the localized accumulation of regulatory T (Treg) cells. Evidence exists that components in commonly consumed foods including vitamins A, D, and E, water-soluble constituents of mushrooms, polyphenolics in fruits and vegetables, and n-3 fatty acids in fish oil can modulate NK cell activities, Treg cell properties, and the interactions between those two cell …
Does The Microbiota Play A Role In The Pathogenesis Of Autoimmune Diseases?, Mairi H. Mclean, Dario Dieguez, Lindsey M. Miller, Howard A. Young
Does The Microbiota Play A Role In The Pathogenesis Of Autoimmune Diseases?, Mairi H. Mclean, Dario Dieguez, Lindsey M. Miller, Howard A. Young
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The microbiota of the human metaorganism is not a mere bystander. These microbes have coevolved with us and are pivotal to normal development and homoeostasis. Dysbiosis of the GI microbiota is associated with many disease susceptibilities, including obesity, malignancy, liver disease and GI pathology such as IBD. It is clear that there is direct and indirect crosstalk between this microbial community and host immune response. However, the precise mechanism of this microbial influence in disease pathogenesis remains elusive and is now a major research focus. There is emerging literature on the role of the microbiota in the pathogenesis of autoimmune …
Nos Inhibition Modulates Immune Polarization And Improves Radiation-Induced Tumor Growth Delay, Lisa A. Ridnour, Robert Y.S. Cheng, Jonathan M. Weiss, Sukhbir Kaur, David R. Soto-Pantoja, Debashree Basudhar, Julie L. Heinecke, C. Andrew Stewart, William Degraff, Anastasia L. Sowers, Angela Thetford, Aparna H. Kesarwala, David D. Roberts, Howard A. Young, James B. Mitchell, Giorgio Trinchieri, Robert H. Wiltrout, David A. Wink
Nos Inhibition Modulates Immune Polarization And Improves Radiation-Induced Tumor Growth Delay, Lisa A. Ridnour, Robert Y.S. Cheng, Jonathan M. Weiss, Sukhbir Kaur, David R. Soto-Pantoja, Debashree Basudhar, Julie L. Heinecke, C. Andrew Stewart, William Degraff, Anastasia L. Sowers, Angela Thetford, Aparna H. Kesarwala, David D. Roberts, Howard A. Young, James B. Mitchell, Giorgio Trinchieri, Robert H. Wiltrout, David A. Wink
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Nitric oxide synthases (NOS) are important mediators of progrowth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation. Herein, we show enhanced radiation-induced (10 Gy) tumor growth delay in a syngeneic model (C3H) but not immunosuppressed (Nu/Nu) squamous cell carcinoma tumor-bearing mice treated post-IR with the constitutive NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). These results suggest a requirement of T cells for improved radiation tumor response. In …
Sera From Patients With Active Systemic Lupus Erythematosus Patients Enhance The Toll-Like Receptor 4 Response In Monocyte Subsets, Tiago Carvalheiro, Diane Gomes, Ligia A. Pinto, Luis Inês, Ana Lopes, Ana Henriques, Susana Pedreiro, António Martinho, Hélder Trindade, Howard A. Young, José António Pereira Da Silva, Artur Paiva
Sera From Patients With Active Systemic Lupus Erythematosus Patients Enhance The Toll-Like Receptor 4 Response In Monocyte Subsets, Tiago Carvalheiro, Diane Gomes, Ligia A. Pinto, Luis Inês, Ana Lopes, Ana Henriques, Susana Pedreiro, António Martinho, Hélder Trindade, Howard A. Young, José António Pereira Da Silva, Artur Paiva
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Background: Systemic Lupus Erythematosus (SLE) is an auto-immune disease whose complex pathogenesis remains unraveled. Here we aim to explore the inflammatory ability of SLE patients' sera upon peripheral blood (PB) monocyte subsets and myeloid dendritic cells (mDCs) obtained from healthy donors. Methods: In this study we included 11 SLE patients with active disease (ASLE), 11 with inactive disease (ISLE) and 10 healthy controls (HC). PB from healthy donors was stimulated with patients' sera, toll-like receptor (TLR) 4 ligand - lipopolysaccharide or both. The intracellular production of TNF-α was evaluated in classical, non-classical monocytes and mDCs, using flow cytometry. TNF-α mRNA …
Short Course In The Microbiome, Kimberly Falana, Rob Knight, Camilia R. Martin, Romina Goldszmid, K. Leigh Greathouse, Joanne Gere, Howard Young, Winston Patrick Kuo
Short Course In The Microbiome, Kimberly Falana, Rob Knight, Camilia R. Martin, Romina Goldszmid, K. Leigh Greathouse, Joanne Gere, Howard Young, Winston Patrick Kuo
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Over the past decade, it has become evident that the microbiome is an important environmental factor that affects many physiological processes, such as cell proliferation and differentiation, behaviour, immune function and metabolism. More importantly, it may contribute to a wide variety of diseases, including cancer, inflammatory diseases, metabolic diseases and responses to pathogens. We expect that international, integrative and interdisciplinary translational research teams, along with the emergence of FDA-approved platforms, will set the framework for microbiome-based therapeutics and diagnostics. We recognize that the microbiome ecosystem offers new promise for personalized/precision medicine and targeted treatment for a variety of diseases. The …
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
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
Public Health Resources
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
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
Public Health Resources
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
Interferons: Success In Anti-Viral Immunotherapy, Fan Ching Lin, Howard A. Young
Public Health Resources
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 …