scholarly journals ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3813-3820 ◽  
Author(s):  
Valentina Nardi ◽  
Olaia Naveiras ◽  
Mohammad Azam ◽  
George Q. Daley
Keyword(s):  
Murine Model ◽  
Consensus Sequence ◽  
Myelogenous Leukemia ◽  
Transformed Cells ◽  
Type I ◽  
Immune Protection ◽  
Immune Mechanism ◽  
Type I Ifns ◽  
New Strategies

Abstract Interferon (IFN) is effective at inducing complete remissions in patients with chronic myelogenous leukemia (CML), and evidence supports an immune mechanism. Here we show that the type I IFNs (alpha and beta) regulate expression of the IFN consensus sequence-binding protein (ICSBP) in BCR-ABL–transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of BCR-ABL–induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the type I IFNs and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the antileukemic response of IFNs suggest new strategies for immunotherapy of CML.

A Critical Role for CCL Chemokines in the Immuno-Protection Induced by Type I Interferons and IRF8/ICSBP Against Bcr/Abl-Induced Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1001-1001
Author(s):  
Valentina Nardi ◽  
Olaia Naveiras ◽  
Mohammad Azam ◽  
George Q. Daley
Keyword(s):  
Transcriptional Profiling ◽  
Consensus Sequence ◽  
Critical Role ◽  
Myelogenous Leukemia ◽  
Type I Interferons ◽  
Leukemic Cells ◽  
Transformed Cells ◽  
Type I ◽  
Type I Ifns ◽  
Ifn Alpha

Abstract Until recently, the mainstay of Chronic Myelogenous Leukemia (CML) therapy was Interferon (IFN) alpha, which in a minority of patients induces long lasting cytogenetic remission. While the exact mechanism of action of IFN alpha in CML is still obscure, it is clear that the clinical response to IFN alpha correlates with immune system reactivity against leukemic clones. As minimal molecular disease often persists despite the use of imatinib and new Bcr-Abl inhibitors, immunotherapy remains an appealing adjunct to molecularly targeted inhibitors in CML therapy. We have shown that IRF8/ICSBP (Interferon Consensus Sequence Binding Protein) expression in Bcr-Abl transformed cells prevents their capacity to form a lethal leukemia when injected into mice, and that this protection is mediated by a long-lasting and potent CD8+ response against unknown epitopes on the leukemic cells. We hypothesized that the protection mediated by IRF8/ICSBP might be related to the anti-leukemic effects of IFN alpha. We now find that Type I IFNs like IFN alpha regulate IRF8/ICSBP expression in mouse and human cells and in Bcr-Abl transformed cells. Furthermore, type I IFNs can substitute for ICSBP in inducing the anti-leukemic immunity against Bcr-Abl transformed cells. Transcriptional profiling of cells expressing ICSBP, Bcr-Abl, or both ICSBP and Bcr-Abl identified two chemokines, CCL6 and CCL9, which were associated with the immune protection induced by IRF8/ICSBP expression. Type I IFNs and IRF8/ICSBP induce the expression of these chemokines in cells transformed with Bcr-Abl. RNAi-mediated inhibition experiments in our mouse model of CML show that these chemokines are required for the IRF8/ICSBP-mediated CD8+ anti-leukemic response to the Bcr-Abl transformed cells, suggesting that these chemokines could be exploited for immunotherapy in combination with existing Bcr-Abl peptide vaccines.

scholarly journals Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Jonathan Lopez ◽  
Marine Mommert ◽  
William Mouton ◽  
Andrés Pizzorno ◽  
Karen Brengel-Pesce ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Type I ◽  
Nasal Type ◽  
Viral Loads ◽  
Functional Assays ◽  
Human Airway Epithelium ◽  
Type I Ifns ◽  
Antiviral Effects ◽  
Nasopharyngeal Mucosa

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3–dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.

scholarly journals The Role of Cutaneous Type I IFNs in Autoimmune and Autoinflammatory Diseases

2020 ◽  
Vol 205 (11) ◽  
pp. 2941-2950
Author(s):  
Jessica L. Turnier ◽  
J. Michelle Kahlenberg
Keyword(s):  
Autoinflammatory Diseases ◽  
Type I ◽  
Type I Ifns

scholarly journals Species-dependent role of type I IFNs and IL-12 in the CTL response induced by humanized CpG complexed with β-glucan

2016 ◽  
Vol 46 (5) ◽  
pp. 1142-1151 ◽  
Author(s):  
Kouji Kobiyama ◽  
Burcu Temizoz ◽  
Tomohiro Kanuma ◽  
Koji Ozasa ◽  
Masatoshi Momota ◽  
...  
Keyword(s):  
Type I ◽  
Ctl Response ◽  
Type I Ifns

scholarly journals Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity

2010 ◽  
Vol 84 (13) ◽  
pp. 6549-6563 ◽  
Author(s):  
Erin L. Lousberg ◽  
Cara K. Fraser ◽  
Michael G. Tovey ◽  
Kerrilyn R. Diener ◽  
John D. Hayball
Keyword(s):  
Immune Responses ◽  
Plasmacytoid Dendritic Cell ◽  
Type I Interferons ◽  
Interleukin 12 ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Fowlpox Virus ◽  
Adaptive Immune ◽  
Type I Ifns

ABSTRACT Type I interferons (IFNs) are considered to be important mediators of innate immunity due to their inherent antiviral activity, ability to drive the transcription of a number of genes involved in viral clearance, and their role in the initiation of innate and adaptive immune responses. Due to the central role of type I IFNs, we sought to determine their importance in the generation of immunity to a recombinant vaccine vector fowlpox virus (FPV). In analyzing the role of type I IFNs in immunity to FPV, we show that they are critical to the secretion of a number of innate and proinflammatory cytokines, including type I IFNs themselves as well as interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β, and that deficiency leads to enhanced virus-mediated antigen expression. Interestingly, however, type I IFNs were not required for adaptive immune responses to recombinant FPV even though plasmacytoid dendritic cells (pDCs), the primary producers of type I IFNs, have been shown to be requisite for this to occur. Furthermore, we provide evidence that the importance of pDCs may lie in their ability to capture and present virally derived antigen to T cells rather than in their capacity as professional type I IFN-producing cells.

scholarly journals Role of PKR and Type I IFNs in Viral Control during Primary and Secondary Infection

2010 ◽  
Vol 6 (6) ◽  
pp. e1000966 ◽  
Author(s):  
Yumi Nakayama ◽  
Erin H. Plisch ◽  
Jeremy Sullivan ◽  
Chester Thomas ◽  
Charles J. Czuprynski ◽  
...  
Keyword(s):  
Secondary Infection ◽  
Type I ◽  
Viral Control ◽  
Type I Ifns

scholarly journals Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

2019 ◽  
Author(s):  
Jie Wang ◽  
Tariq Hussain ◽  
Kai Zhang ◽  
Yi Liao ◽  
Jiao Yao ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Defense Mechanism ◽  
Histopathological Examination ◽  
Bacterial Count ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Pathways ◽  
Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR was performed to detect the expression of Type I IFNs and related genes. M. bovis induced lung lesions were assessed by histopathological examination and viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell recruitment and activation in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

scholarly journals Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

2020 ◽  
Author(s):  
Daisy X. Ji ◽  
Kristen C. Witt ◽  
Dmitri I. Kotov ◽  
Shally R. Margolis ◽  
Alexander Louie ◽  
...  
Keyword(s):  
Immune Responses ◽  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Transcriptional Regulator ◽  
Type I Interferons ◽  
Type I ◽  
Viral Immunity ◽  
Type I Ifns

AbstractType I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. How type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections, remains poorly understood. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to many bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that functions to repress the expression of type I IFNs during bacterial infections. We generated Sp140−/− mice and find they are susceptible to infection by diverse bacteria, including Listeria monocytogenes, Legionella pneumophila, and Mycobacterium tuberculosis. Susceptibility of Sp140−/− mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar−/−). Our results implicate Sp140 as an important repressor of type I IFNs that is essential for resistance to bacterial infections.

scholarly journals B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

2014 ◽  
Vol 83 (2) ◽  
pp. 743-758 ◽  
Author(s):  
Teri R. Hoyt ◽  
Erin Dobrinen ◽  
Irina Kochetkova ◽  
Nicole Meissner
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Lung Infection ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
On Demand ◽  
Type I Ifns

HIV infection results in a complex immunodeficiency due to loss of CD4+T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such asPneumocystis murinapneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity toPneumocystislung infection. We recently also identified B cells as supporters of on-demand hematopoiesis followingPneumocystisinfection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity toPneumocystisinfection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag−/−) developed progressive bone marrow failure following infection, while lymphocyte-competent type I IFN receptor-deficient mice (IFNAR−/−) showed transient bone marrow depression and extramedullary hematopoiesis. Lymphocyte reconstitution of lymphocyte-deficient IFrag−/−mice pointed to B cells as a key player in bone marrow protection. Here we define how B cells protect on-demand hematopoiesis followingPneumocystis lung infection in our model. We demonstrate that adoptive transfer of B cells into IFrag−/−mice protects early hematopoietic progenitor activity during systemic responses toPneumocystisinfection, thus promoting replenishment of depleted bone marrow cells. This activity is independent of CD4+T cell help and B cell receptor specificity and does not require B cell migration to bone marrow. Furthermore, we show that B cells protect on-demand hematopoiesis in part by induction of interleukin-10 (IL-10)- and IL-27-mediated mechanisms. Thus, our data demonstrate an important immune modulatory role of B cells duringPneumocystislung infection that complement the modulatory role of type I IFNs to prevent systemic complications.

scholarly journals Control of coronavirus infection through plasmacytoid dendritic-cell–derived type I interferon

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1131-1137 ◽  
Author(s):  
Luisa Cervantes-Barragan ◽  
Roland Züst ◽  
Friedemann Weber ◽  
Martin Spiegel ◽  
Karl S. Lang ◽  
...  
Keyword(s):  
Response Pattern ◽  
Hepatitis Virus ◽  
Rna Virus ◽  
Plasmacytoid Dendritic Cell ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifns ◽  
Rapid Production ◽  
Coronavirus Infection

Abstract This study demonstrates a unique and crucial role of plasmacytoid dendritic cells (pDCs) and pDC-derived type I interferons (IFNs) in the pathogenesis of mouse coronavirus infection. pDCs controlled the fast replicating mouse hepatitis virus (MHV) through the immediate production of type I IFNs. Recognition of MHV by pDCs was mediated via TLR7 ensuring a swift IFN-α production following encounter with this cytopathic RNA virus. Furthermore, the particular type I IFN response pattern was not restricted to the murine coronavirus, but was also found in infection with the highly cytopathic human severe acute respiratory syndrome (SARS) coronavirus. Taken together, our results suggest that rapid production of type I IFNs by pDCs is essential for the control of potentially lethal coronavirus infections.

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