- Email: [email protected]
CS4-3 IFN-β modulates Th17 induction in EAE
Cytokine 52 (2010) 40–41
Contents lists available at ScienceDirect
Cytokine journal homepage: www.elsevier.com/locate/issn/10434666
Interferons and Treatment of Diseases CS4-1 PAMP signaling and mechanisms of IFN actions against virus infection Michael Gale Jr., Department of Immunology, University of Washington, Seattle, WA, USA Innate immune defenses are essential for the control of virus infection and are triggered through host recognition of macromolecular motifs known as pathogenassociated molecular patterns (PAMPs). Type 1 interferons (IFN) are central products of PAMP signaling of which they impart potent antiviral and antiproliferative actions to cells. These properties of PAMP signaling and IFN form the basis of their therapeutic applications. As such, PAMP/host factor interactions are now being assessed for application as immunotherapy and use as vaccine adjuvants. Moreover, IFN is used as a major antiviral to treat chronic hepatitis C virus (HCV) infection, and is approved as a therapy for a variety of other pathologies, including cancers and microbial infections. A major focus in our laboratory is to define the mechanisms by which RNA viruses, including HCV are observed by the host through processes of PAMP-host factor interactions to drive the immune response to infection. We are also focused on understanding how IFN functions to suppress HCV infection. To this end we have identified specific PAMP motifs of HCV that impart RIG-I interaction and innate immune signaling that drives IFN expression. We now can report that IFN suppresses HCV infection in part through the actions of specific interferon-stimulated gene products. We will also report on our progress in developing drugs that confer RIG-I signaling, and how these drugs can used as vaccine adjuvants or antivirals to modulate virus infection and immunity.
encephalomyelitis model for MS, mice null for IFN-b, IFN-b / , exhibit an earlier onset and a more rapid progression of disease compared to IFN-b+/+ mice. IFNb / mice exhibit increased numbers of Th17 cells in their draining lymph nodes (DLN) as early as 4 days after disease induction, with significantly elevated numbers compared with IFN-b+/+ mice by day 10. Notably, these Th17 cells have been implicated as critical effectors in autoimmune diseases, including MS. Moreover, immunohistochemistry confirms abundant Th17 cells in the DLNs and spinal cords of IFN-b / mice at later stages of disease. Additionally, CD4+ T cells derived from IFN-b / mice exhibit a greater propensity to polarize toward Th17 lineage commitment ex vivo, following relevant cytokine stimulation. These effects are blocked by the addition of recombinant IFN-b which leads to global downregulation of Th17 associated genes. Increased Th17 cell polarization may be driven by DCs, as DCs derived from IFN-b / mice induce greater proliferation of T cells derived from either IFN-b+/+ or IFN-b / mice, compared with DCs derived from IFN-b+/+ mice. Finally, gene expression studies in bone marrow macrophages from IFN-b+/ + and IFN-b / mice have revealed differential expression of pro-inflammatory and Th17-polarizing cytokines. Viewed altogether, the data indicate that IFN-b acts to suppress the generation of autoimmune inducing Th17 cells during the development of EAE. doi:10.1016/j.cyto.2010.07.171
doi:10.1016/j.cyto.2010.07.169
CS4-2 Efficacy of pegylated interferon b-1a in human cancer xenograft models Ingrid Joseph 1, Antonio Boccia 1, Cyrus Virata 1, Grace Yco 1, Jim Gamez 1, Kathy Wortham 1, Rebecca Kelly 1, Keli Perron 1, Lu Yang 1, Xiamei Zhang 1, Nuzhat Pathan 2, Nicki English 2, Monica Holcomb 2, Jennifer L. Gardner 3, Bob Dunstan 4, Donald Bennett 5, Daniel J. Lindner 6, Darren P. Baker 7, 1 Department of Oncopharmacology, Cambridge, MA, USA, 2 Department of Cancer Discovery, Cambridge, MA, USA, 3 Department of Discovery Cancer Therapeutics, Cambridge, MA, USA, 4 Department of Comparative Pathology, Cambridge, MA, USA, 5 Department of Biostatistics, Cambridge, MA, USA, 6 Cleveland Clinic, Cleveland, OH, USA, 7 Department of Drug Discovery, Biogenidec Inc., Cambridge, MA, USA Interferon beta-1a mediates a plethora of biological effects including antiviral, antiproliferative, antiangiogenic, and immunomodulatory responses. To determine whether PEGylated interferon beta-1a could inhibit the growth of human tumors, and whether tumor growth inhibition by known inhibitors could be augmented by PEGylated interferon beta-1a, monotherapy and combination studies were carried out in nude and SCID mice. The results of these studies and the potential use of PEGylated interferon beta-1a for the treatment of cancer will be discussed. doi:10.1016/j.cyto.2010.07.170
CS4-3 IFN-b modulates Th17 induction in EAE Leesa M. Pennell 1,2, Carole L. Galligan 1,2, Eleanor N. Fish 1,2, 1 Department of Immunology, University of Toronto, Toronto, ON, Canada, 2 Toronto General Research Institute, University Health Network, Toronto, ON, Canada Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation and demyelination of nerve fibers. Interferon (IFN)-b was the first approved therapy for relapsing-remitting MS more than 10 years ago, however, its mechanism of action remains ill-defined. Using a murine experimental autoimmune
CS4-4 Cell type-specific responses to IFN-b: Implications for understanding the mechanism of IFN-b therapy in multiple sclerosis Anette H.H. van Boxel-Dezaire 1, Elizabeth Fisher 2, Richard M. Ransohoff 3, Richard A. Rudick 4, George R. Stark 1, 1 Molecular Genetics, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio, USA, 2 Biomedical Engineering, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio, USA, 3 Neuroinflammation Research Center, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio, USA, 4 Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA IFN-b is a major treatment for multiple sclerosis (MS), but is not effective in a significant portion of patients, and the molecular mechanism of successful treatment is still unknown. Our goal was to study the signaling response in primary leukocytes of healthy subjects or MS patients after stimulation with IFN-b in vitro or after IM injection with IFN-b1a, respectively. We used flow cytometry to measure the amounts of IFN-b-induced phosphorylated P38MAPK and STATs 1, 3 and 5 in leukocytes present in whole blood. In contrast to monocytes and CD8+ T cells of healthy individuals, few B cells activated STAT1, a finding that could not be explained by decreased STAT1 or IFNAR2 levels. Micro-array and RT-PCR analysis revealed only PY-STAT1-dependent pro-apoptotic mRNA induction in monocytes and not in B cells. These data show that ISGF3 or STAT1 homodimers are not the main activators of gene expression in primary human B cells of healthy subjects. Notably, B cells and CD4+ T cells activated STAT5, which has effects on cell survival opposite from those of activated STAT1. We are currently investigating the mechanism that prevents most B cells from activating STAT1 after IFN-a/b stimulation. Remarkably, leukocyte subsets of MS patients showed different STAT and P38MAPK activation patterns after IM IFN-b1a injection, which might explain the cell type-specific induction of TRAIL and other genes by type I IFNs. In conclusion, our results show cell type-specific signaling responses after stimulation in vitro and after IFN-b injection in MS patients, which may relate to mechanisms of action of IFN-b therapy in MS. We also found some differences between MS patients within given leukocyte subsets, and are in the process of determining whether differential STAT and kinase activation in blood cells by IFN-b injection correlates with response to therapy, defined as MRI stability after start of treatment. doi:10.1016/j.cyto.2010.07.172
Contents lists available at ScienceDirect
Cytokine journal homepage: www.elsevier.com/locate/issn/10434666
Interferons and Treatment of Diseases CS4-1 PAMP signaling and mechanisms of IFN actions against virus infection Michael Gale Jr., Department of Immunology, University of Washington, Seattle, WA, USA Innate immune defenses are essential for the control of virus infection and are triggered through host recognition of macromolecular motifs known as pathogenassociated molecular patterns (PAMPs). Type 1 interferons (IFN) are central products of PAMP signaling of which they impart potent antiviral and antiproliferative actions to cells. These properties of PAMP signaling and IFN form the basis of their therapeutic applications. As such, PAMP/host factor interactions are now being assessed for application as immunotherapy and use as vaccine adjuvants. Moreover, IFN is used as a major antiviral to treat chronic hepatitis C virus (HCV) infection, and is approved as a therapy for a variety of other pathologies, including cancers and microbial infections. A major focus in our laboratory is to define the mechanisms by which RNA viruses, including HCV are observed by the host through processes of PAMP-host factor interactions to drive the immune response to infection. We are also focused on understanding how IFN functions to suppress HCV infection. To this end we have identified specific PAMP motifs of HCV that impart RIG-I interaction and innate immune signaling that drives IFN expression. We now can report that IFN suppresses HCV infection in part through the actions of specific interferon-stimulated gene products. We will also report on our progress in developing drugs that confer RIG-I signaling, and how these drugs can used as vaccine adjuvants or antivirals to modulate virus infection and immunity.
encephalomyelitis model for MS, mice null for IFN-b, IFN-b / , exhibit an earlier onset and a more rapid progression of disease compared to IFN-b+/+ mice. IFNb / mice exhibit increased numbers of Th17 cells in their draining lymph nodes (DLN) as early as 4 days after disease induction, with significantly elevated numbers compared with IFN-b+/+ mice by day 10. Notably, these Th17 cells have been implicated as critical effectors in autoimmune diseases, including MS. Moreover, immunohistochemistry confirms abundant Th17 cells in the DLNs and spinal cords of IFN-b / mice at later stages of disease. Additionally, CD4+ T cells derived from IFN-b / mice exhibit a greater propensity to polarize toward Th17 lineage commitment ex vivo, following relevant cytokine stimulation. These effects are blocked by the addition of recombinant IFN-b which leads to global downregulation of Th17 associated genes. Increased Th17 cell polarization may be driven by DCs, as DCs derived from IFN-b / mice induce greater proliferation of T cells derived from either IFN-b+/+ or IFN-b / mice, compared with DCs derived from IFN-b+/+ mice. Finally, gene expression studies in bone marrow macrophages from IFN-b+/ + and IFN-b / mice have revealed differential expression of pro-inflammatory and Th17-polarizing cytokines. Viewed altogether, the data indicate that IFN-b acts to suppress the generation of autoimmune inducing Th17 cells during the development of EAE. doi:10.1016/j.cyto.2010.07.171
doi:10.1016/j.cyto.2010.07.169
CS4-2 Efficacy of pegylated interferon b-1a in human cancer xenograft models Ingrid Joseph 1, Antonio Boccia 1, Cyrus Virata 1, Grace Yco 1, Jim Gamez 1, Kathy Wortham 1, Rebecca Kelly 1, Keli Perron 1, Lu Yang 1, Xiamei Zhang 1, Nuzhat Pathan 2, Nicki English 2, Monica Holcomb 2, Jennifer L. Gardner 3, Bob Dunstan 4, Donald Bennett 5, Daniel J. Lindner 6, Darren P. Baker 7, 1 Department of Oncopharmacology, Cambridge, MA, USA, 2 Department of Cancer Discovery, Cambridge, MA, USA, 3 Department of Discovery Cancer Therapeutics, Cambridge, MA, USA, 4 Department of Comparative Pathology, Cambridge, MA, USA, 5 Department of Biostatistics, Cambridge, MA, USA, 6 Cleveland Clinic, Cleveland, OH, USA, 7 Department of Drug Discovery, Biogenidec Inc., Cambridge, MA, USA Interferon beta-1a mediates a plethora of biological effects including antiviral, antiproliferative, antiangiogenic, and immunomodulatory responses. To determine whether PEGylated interferon beta-1a could inhibit the growth of human tumors, and whether tumor growth inhibition by known inhibitors could be augmented by PEGylated interferon beta-1a, monotherapy and combination studies were carried out in nude and SCID mice. The results of these studies and the potential use of PEGylated interferon beta-1a for the treatment of cancer will be discussed. doi:10.1016/j.cyto.2010.07.170
CS4-3 IFN-b modulates Th17 induction in EAE Leesa M. Pennell 1,2, Carole L. Galligan 1,2, Eleanor N. Fish 1,2, 1 Department of Immunology, University of Toronto, Toronto, ON, Canada, 2 Toronto General Research Institute, University Health Network, Toronto, ON, Canada Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation and demyelination of nerve fibers. Interferon (IFN)-b was the first approved therapy for relapsing-remitting MS more than 10 years ago, however, its mechanism of action remains ill-defined. Using a murine experimental autoimmune
CS4-4 Cell type-specific responses to IFN-b: Implications for understanding the mechanism of IFN-b therapy in multiple sclerosis Anette H.H. van Boxel-Dezaire 1, Elizabeth Fisher 2, Richard M. Ransohoff 3, Richard A. Rudick 4, George R. Stark 1, 1 Molecular Genetics, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio, USA, 2 Biomedical Engineering, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio, USA, 3 Neuroinflammation Research Center, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio, USA, 4 Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA IFN-b is a major treatment for multiple sclerosis (MS), but is not effective in a significant portion of patients, and the molecular mechanism of successful treatment is still unknown. Our goal was to study the signaling response in primary leukocytes of healthy subjects or MS patients after stimulation with IFN-b in vitro or after IM injection with IFN-b1a, respectively. We used flow cytometry to measure the amounts of IFN-b-induced phosphorylated P38MAPK and STATs 1, 3 and 5 in leukocytes present in whole blood. In contrast to monocytes and CD8+ T cells of healthy individuals, few B cells activated STAT1, a finding that could not be explained by decreased STAT1 or IFNAR2 levels. Micro-array and RT-PCR analysis revealed only PY-STAT1-dependent pro-apoptotic mRNA induction in monocytes and not in B cells. These data show that ISGF3 or STAT1 homodimers are not the main activators of gene expression in primary human B cells of healthy subjects. Notably, B cells and CD4+ T cells activated STAT5, which has effects on cell survival opposite from those of activated STAT1. We are currently investigating the mechanism that prevents most B cells from activating STAT1 after IFN-a/b stimulation. Remarkably, leukocyte subsets of MS patients showed different STAT and P38MAPK activation patterns after IM IFN-b1a injection, which might explain the cell type-specific induction of TRAIL and other genes by type I IFNs. In conclusion, our results show cell type-specific signaling responses after stimulation in vitro and after IFN-b injection in MS patients, which may relate to mechanisms of action of IFN-b therapy in MS. We also found some differences between MS patients within given leukocyte subsets, and are in the process of determining whether differential STAT and kinase activation in blood cells by IFN-b injection correlates with response to therapy, defined as MRI stability after start of treatment. doi:10.1016/j.cyto.2010.07.172