29 results on '"Duhan, Vikas"'
Search Results
2. Replication of Influenza A Virus in Secondary Lymphatic Tissue Contributes to Innate Immune Activation.
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Friedrich SK, Schmitz R, Bergerhausen M, Lang J, Duhan V, Hardt C, Tenbusch M, Prinz M, Asano K, Bhat H, Hamdan TA, Lang PA, and Lang KS
- Abstract
The replication of viruses in secondary lymphoid organs guarantees sufficient amounts of pattern-recognition receptor ligands and antigens to activate the innate and adaptive immune system. Viruses with broad cell tropism usually replicate in lymphoid organs; however, whether a virus with a narrow tropism relies on replication in the secondary lymphoid organs to activate the immune system remains not well studied. In this study, we used the artificial intravenous route of infection to determine whether Influenza A virus (IAV) replication can occur in secondary lymphatic organs (SLO) and whether such replication correlates with innate immune activation. Indeed, we found that IAV replicates in secondary lymphatic tissue. IAV replication was dependent on the expression of Sialic acid residues in antigen-presenting cells and on the expression of the interferon-inhibitor UBP43 ( Usp18 ). The replication of IAV correlated with innate immune activation, resulting in IAV eradication. The genetic deletion of Usp18 curbed IAV replication and limited innate immune activation. In conclusion, we found that IAV replicates in SLO, a mechanism which allows innate immune activation.
- Published
- 2021
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3. Innate myeloid cells in the tumor microenvironment.
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Duhan V and Smyth MJ
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- Animals, Humans, Immunity, Innate, Neoplasms immunology, Tumor Microenvironment, Immunotherapy methods, Lymphocytes, Tumor-Infiltrating immunology, Myeloid-Derived Suppressor Cells immunology, Neoplasms therapy
- Abstract
Cancer immunotherapies are receiving increasing approval in the clinic, but still only a fraction of patients benefit long-term. Understanding the most important mechanisms of immunotherapeutic resistance is critical for broader utility and benefit of cancer immunotherapy. While the tumor microenvironment (TME) is made up of many cell types, immunosuppressive monocytes/macrophages, granulocytes and myeloid derived suppressor cells interact with, and play a critical role in regulating the anti-tumor lymphocyte effector cells that mediate effective immunotherapies. Herein, we discuss the latest research that has identified and compared the importance of pro-tumor and immunosuppressive mechanisms that tumor infiltrating myeloid cells employ. Exploiting this new information may help to develop totally novel therapies to boost contemporary cancer immunotherapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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4. Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells.
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Duhan V, Khairnar V, Kitanovski S, Hamdan TA, Klein AD, Lang J, Ali M, Adomati T, Bhat H, Friedrich SK, Li F, Krebs P, Futerman AH, Addo MM, Hardt C, Hoffmann D, Lang PA, and Lang KS
- Subjects
- Animals, Antigens, CD genetics, Cells, Cultured, Dendritic Cells immunology, Dendritic Cells metabolism, Disease Models, Animal, Genome-Wide Association Study, Host-Pathogen Interactions, Integrin alpha Chains genetics, Mice, 129 Strain, Mice, Inbred AKR, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred NOD, Mice, Knockout, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Receptor, Interferon alpha-beta genetics, Receptor, Interferon alpha-beta metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Vesicular Stomatitis genetics, Vesicular Stomatitis immunology, Vesicular Stomatitis metabolism, Vesiculovirus growth & development, Virus Replication, Mice, Antigens, CD metabolism, Dendritic Cells virology, Immunity, Innate, Integrin alpha Chains metabolism, Interferon Type I metabolism, Vesicular Stomatitis virology, Vesiculovirus pathogenicity
- Abstract
Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E ( Itgae , CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Duhan, Khairnar, Kitanovski, Hamdan, Klein, Lang, Ali, Adomati, Bhat, Friedrich, Li, Krebs, Futerman, Addo, Hardt, Hoffmann, Lang and Lang.)
- Published
- 2021
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5. Arenavirus Induced CCL5 Expression Causes NK Cell-Mediated Melanoma Regression.
- Author
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Bhat H, Zaun G, Hamdan TA, Lang J, Adomati T, Schmitz R, Friedrich SK, Bergerhausen M, Cham LB, Li F, Ali M, Zhou F, Khairnar V, Duhan V, Brandenburg T, Machlah YM, Schiller M, Berry A, Xu H, Vollmer J, Häussinger D, Thier B, Pandyra AA, Schadendorf D, Paschen A, Schuler M, Lang PA, and Lang KS
- Subjects
- Animals, Cell Line, Tumor, Heterografts, Humans, Lymphocytic choriomeningitis virus immunology, Mice, Oncolytic Viruses immunology, Arenaviridae Infections immunology, Chemokine CCL5 immunology, Immunotherapy methods, Killer Cells, Natural immunology, Melanoma immunology
- Abstract
Immune activation within the tumor microenvironment is one promising approach to induce tumor regression. Certain viruses including oncolytic viruses such as the herpes simplex virus (HSV) and non-oncolytic viruses such as the lymphocytic choriomeningitis virus (LCMV) are potent tools to induce tumor-specific immune activation. However, not all tumor types respond to viro- and/or immunotherapy and mechanisms accounting for such differences remain to be defined. In our current investigation, we used the non-cytopathic LCMV in different human melanoma models and found that melanoma cell lines produced high levels of CCL5 in response to immunotherapy. In vivo , robust CCL5 production in LCMV infected Ma-Mel-86a tumor bearing mice led to recruitment of NK cells and fast tumor regression. Lack of NK cells or CCL5 abolished the anti-tumoral effects of immunotherapy. In conclusion, we identified CCL5 and NK cell-mediated cytotoxicity as new factors influencing melanoma regression during virotherapy., (Copyright © 2020 Bhat, Zaun, Hamdan, Lang, Adomati, Schmitz, Friedrich, Bergerhausen, Cham, Li, Ali, Zhou, Khairnar, Duhan, Brandenburg, Machlah, Schiller, Berry, Xu, Vollmer, Häussinger, Thier, Pandyra, Schadendorf, Paschen, Schuler, Lang and Lang.)
- Published
- 2020
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6. Usp18 Expression in CD169 + Macrophages is Important for Strong Immune Response after Vaccination with VSV-EBOV.
- Author
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Friedrich SK, Schmitz R, Bergerhausen M, Lang J, Cham LB, Duhan V, Häussinger D, Hardt C, Addo M, Prinz M, Asano K, Lang PA, and Lang KS
- Abstract
Ebola virus epidemics can be effectively limited by the VSV-EBOV vaccine (Ervebo) due to its rapid protection abilities; however, side effects prevent the broad use of VSV-EBOV as vaccine. Mechanisms explaining the efficient immune activation after single injection with the VSV-EBOV vaccine remain mainly unknown. Here, using the clinically available VSV-EBOV vaccine (Ervebo), we show that the cell-intrinsic expression of the interferon-inhibitor Usp18 in CD169
+ macrophages is one important factor modulating the anti-Ebola virus immune response. The absence of Usp18 in CD169+ macrophages led to the reduced local replication of VSV-EBOV followed by a diminished innate as well as adaptive immune response. In line, CD169 -Cre+/ki x Usp18fl/fl mice showed reduced innate and adaptive immune responses against the VSV wildtype strain and died quickly after infection, suggesting that a lack of Usp18 makes mice more susceptible to the side effects of the VSV vector. In conclusion, our study shows that Usp18 expression in CD169+ macrophages is one important surrogate marker for effective vaccination against VSV-EBOV, and probably other VSV-based vaccines also.- Published
- 2020
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7. Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection.
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Adomati T, Cham LB, Hamdan TA, Bhat H, Duhan V, Li F, Ali M, Lang E, Huang A, Naser E, Khairnar V, Friedrich SK, Lang J, Friebus-Kardash J, Bergerhausen M, Schiller M, Machlah YM, Lang F, Häussinger D, Ferencik S, Hardt C, Lang PA, and Lang KS
- Subjects
- Acute Disease, Animals, Antiviral Agents metabolism, Cell Death drug effects, Dexamethasone pharmacology, Enzyme Activation drug effects, Interleukin-10 metabolism, Mice, Inbred C57BL, Signal Transduction drug effects, Vesicular Stomatitis virology, Clonal Anergy drug effects, Immunity, Innate drug effects, Vesicular Stomatitis enzymology, Vesicular Stomatitis immunology, Vesiculovirus physiology, c-Mer Tyrosine Kinase metabolism
- Abstract
Infections can result in a temporarily restricted unresponsiveness of the innate immune response, thereby limiting pathogen control. Mechanisms of such unresponsiveness are well studied in lipopolysaccharide tolerance; however, whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here, we find that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days. Innate anergy is associated with induction of apoptotic cells, which activates the Tyro3, Axl, and Mertk (TAM) receptor Mertk and induces high levels of interleukin-10 (IL-10) and transforming growth factor β (TGF-β). Lack of Mertk in Mertk
-/- mice prevents induction of IL-10 and TGF-β, resulting in abrogation of innate anergy. Innate anergy is associated with enhanced VSV replication and poor survival after infection. Mechanistically, Mertk signaling upregulates suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Dexamethasone treatment upregulates Mertk and enhances innate anergy in a Mertk-dependent manner. In conclusion, we identify Mertk as one major regulator of innate tolerance during infection with VSV., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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8. Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease.
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Lang J, Bohn P, Bhat H, Jastrow H, Walkenfort B, Cansiz F, Fink J, Bauer M, Olszewski D, Ramos-Nascimento A, Duhan V, Friedrich SK, Becker KA, Krawczyk A, Edwards MJ, Burchert A, Huber M, Friebus-Kardash J, Göthert JR, Hardt C, Probst HC, Schumacher F, Köhrer K, Kleuser B, Babiychuk EB, Sodeik B, Seibel J, Greber UF, Lang PA, Gulbins E, and Lang KS
- Subjects
- Acid Ceramidase genetics, Animals, Female, Herpes Simplex virology, Humans, Macrophages virology, Mice, Mice, Inbred C57BL, Mice, Knockout, Virus Replication, Acid Ceramidase metabolism, Herpes Simplex enzymology, Herpes Simplex prevention & control, Herpesvirus 1, Human physiology, Macrophages enzymology, Multivesicular Bodies virology
- Abstract
Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1
-/- mice results in replication of HSV-1 and Asah1-/- mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.- Published
- 2020
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9. Map3k14 as a Regulator of Innate and Adaptive Immune Response during Acute Viral Infection.
- Author
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Hamdan TA, Bhat H, Cham LB, Adomati T, Lang J, Li F, Murtaza A, Hardt C, Lang PA, Duhan V, and Lang KS
- Abstract
The replication of virus in secondary lymphoid organs is crucial for the activation of antigen-presenting cells. Balanced viral replication ensures the sufficient availability of antigens and production of cytokines, and both of which are needed for virus-specific immune activation and viral elimination. Host factors that regulate coordinated viral replication are not fully understood. In the study reported here, we identified Map3k14 as an important regulator of enforced viral replication in the spleen while performing genome-wide association studies of various inbred mouse lines in a model of lymphocytic choriomeningitis virus (LCMV) infection. When alymphoplasia mice ( aly/aly, Map3k14
aly/aly , or Nikaly/aly ) , which carry a mutation in Map3k14, were infected with LCMV or vesicular stomatitis virus (VSV), they display early reductions in early viral replication in the spleen, reduced innate and adaptive immune activation, and lack of viral control. Histologically, scant B cells and the lack of CD169+ macrophages correlated with reduced immune activation in Map3k14aly/aly mice. The transfer of wildtype B cells into Map3k14aly/aly mice repopulated CD169+ macrophages, restored enforced viral replication, and resulted in enhanced immune activation and faster viral control.- Published
- 2020
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10. Adipose-Derived Stromal Cells Are Capable of Restoring Bone Regeneration After Post-Traumatic Osteomyelitis and Modulate B-Cell Response.
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Wagner JM, Reinkemeier F, Wallner C, Dadras M, Huber J, Schmidt SV, Drysch M, Dittfeld S, Jaurich H, Becerikli M, Becker K, Rauch N, Duhan V, Lehnhardt M, and Behr B
- Subjects
- Adipose Tissue cytology, Animals, Cell Differentiation, Female, Humans, Male, Mice, Adipose Tissue metabolism, B-Lymphocytes metabolism, Mesenchymal Stem Cells metabolism, Osteomyelitis physiopathology
- Abstract
Bone infections are a frequent cause for large bony defects with a reduced healing capacity. In previous findings, we could already show diminished healing capacity after bone infections, despite the absence of the causing agent, Staphylococcus aureus. Moreover, these bony defects showed reduced osteoblastogenesis and increased osteoclastogenesis, meaning elevated bone resorption ongoing with an elevated B-cell activity. To overcome the negative effects of this postinfectious inflammatory state, we tried to use the regenerative capacity of mesenchymal stem cells derived from adipose tissue (adipose-derived stem cells [ASCs]) to improve bone regeneration and moreover were curious about immunomodulation of applicated stem cells in this setting. Therefore, we used our established murine animal model and applicated ASCs locally after sufficient debridement of infected bones. Bone regeneration and resorption as well as immunological markers were investigated via histology, immunohistochemistry, Western blot, and fluorescence-activated cell scanning (FACS) analysis and μ-computed tomography (CT) analysis. Interestingly, ASCs were able to restore bone healing via elevation of osteoblastogenesis and downregulation of osteoclasts. Surprisingly, stem cells showed an impact on the innate immune system, downregulating B-cell population. In summary, these data provide a fascinating new and innovative approach, supporting bone healing after bacterial infections and moreover gain insights into the complex ceremony of stem cell interaction in terms of bone infection and regeneration. Stem Cells Translational Medicine 2019;8:1084-1091., (© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
- Published
- 2019
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11. Tamoxifen Protects from Vesicular Stomatitis Virus Infection.
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Cham LB, Friedrich SK, Adomati T, Bhat H, Schiller M, Bergerhausen M, Hamdan T, Li F, Machlah YM, Ali M, Duhan V, Lang KS, Friebus-Kardash J, and Bezgovsek J
- Abstract
Background: Tamoxifen (TAM) is an estrogen-receptor antagonist, widely used in the adjuvant treatment of early stage estrogen-sensitive breast cancer. Several studies have revealed new biological targets of TAM that mediate the estrogen receptor independent activities of the drug. Recently, the antiviral activity of TAM on replication of human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Herpes simplex virus (HSV-1) in vitro was described. In the current study, we aimed to investigate the effect of TAM on infection with vesicular stomatitis virus (VSV)., Methods: Vero cells were treated with different concentrations of TAM for 24 h and then infected with VSV. Additionally, C57BL/6 mice were pretreated with 4 mg TAM, one day and three days before infection with VSV. Results: Treatment of Vero cells with TAM suppressed the viral replication of VSV in vitro and in vivo. The inhibitory effect of TAM on VSV replication correlated with an enhanced interferon-I response and stimulation of macrophages. Conclusions: TAM was identified as being capable to protect from VSV infection in vitro and in vivo. Consequently, this antiviral function (as an advantageous side-effect of TAM) might give rise to new clinical applications, such as treatment of resistant virus infections, or serve as an add-on to standard antiviral therapy., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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12. The uric acid crystal receptor Clec12A potentiates type I interferon responses.
- Author
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Li K, Neumann K, Duhan V, Namineni S, Hansen AL, Wartewig T, Kurgyis Z, Holm CK, Heikenwalder M, Lang KS, and Ruland J
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- Animals, Cytosol immunology, Cytosol metabolism, DEAD Box Protein 58 immunology, DEAD Box Protein 58 metabolism, Disease Models, Animal, Humans, Immunity, Innate, Interferon Regulatory Factor-3 immunology, Interferon Regulatory Factor-3 metabolism, Interferon Type I metabolism, Lectins, C-Type genetics, Lectins, C-Type immunology, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus immunology, Mice, Mice, Knockout, Pathogen-Associated Molecular Pattern Molecules immunology, Protein Serine-Threonine Kinases immunology, Protein Serine-Threonine Kinases metabolism, RNA immunology, RNA metabolism, Receptors, Mitogen genetics, Receptors, Mitogen immunology, Signal Transduction immunology, Alarmins immunology, Interferon Type I immunology, Lectins, C-Type metabolism, Lymphocytic Choriomeningitis immunology, Receptors, Mitogen metabolism, Uric Acid immunology
- Abstract
The detection of microbes and damaged host cells by the innate immune system is essential for host defense against infection and tissue homeostasis. However, how distinct positive and negative regulatory signals from immune receptors are integrated to tailor specific responses in complex scenarios remains largely undefined. Clec12A is a myeloid cell-expressed inhibitory C-type lectin receptor that can sense cell death under sterile conditions. Clec12A detects uric acid crystals and limits proinflammatory pathways by counteracting the cell-activating spleen tyrosine kinase (Syk). Here, we surprisingly find that Clec12A additionally amplifies type I IFN (IFN-I) responses in vivo and in vitro. Using retinoic acid-inducible gene I (RIG-I) signaling as a model, we demonstrate that monosodium urate (MSU) crystal sensing by Clec12A enhances cytosolic RNA-induced IFN-I production and the subsequent induction of IFN-I-stimulated genes. Mechanistically, Clec12A engages Src kinase to positively regulate the TBK1-IRF3 signaling module. Consistently, Clec12A-deficient mice exhibit reduced IFN-I responses upon lymphocytic choriomeningitis virus (LCMV) infection, which affects the outcomes of these animals in acute and chronic virus infection models. Thus, our results uncover a previously unrecognized connection between an MSU crystal-sensing receptor and the IFN-I response, and they illustrate how the sensing of extracellular damage-associated molecular patterns (DAMPs) can shape the immune response., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)
- Published
- 2019
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13. NK cell-intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection.
- Author
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Duhan V, Hamdan TA, Xu HC, Shinde P, Bhat H, Li F, Al-Matary Y, Häussinger D, Bezgovsek J, Friedrich SK, Hardt C, Lang PA, and Lang KS
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- Acute Disease, Animals, Antigens, Ly genetics, Antigens, Ly immunology, CD8-Positive T-Lymphocytes pathology, Chronic Disease, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Lymphocytic Choriomeningitis genetics, Lymphocytic Choriomeningitis pathology, Mice, Mice, Knockout, Natural Cytotoxicity Triggering Receptor 1 genetics, Natural Cytotoxicity Triggering Receptor 1 immunology, Receptors, Fc genetics, CD8-Positive T-Lymphocytes immunology, Lymphocyte Activation, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Receptors, Fc immunology
- Abstract
During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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14. TLR7 Controls VSV Replication in CD169 + SCS Macrophages and Associated Viral Neuroinvasion.
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Solmaz G, Puttur F, Francozo M, Lindenberg M, Guderian M, Swallow M, Duhan V, Khairnar V, Kalinke U, Ludewig B, Clausen BE, Wagner H, Lang KS, and Sparwasser TD
- Subjects
- Animals, Brain immunology, Brain virology, Macrophages virology, Membrane Glycoproteins genetics, Mice, Mice, Knockout, Rhabdoviridae Infections genetics, Rhabdoviridae Infections pathology, Sialic Acid Binding Ig-like Lectin 1 genetics, Signal Transduction genetics, Signal Transduction immunology, Spinal Cord immunology, Spinal Cord virology, Toll-Like Receptor 7 genetics, Virus Replication genetics, Macrophages immunology, Membrane Glycoproteins immunology, Rhabdoviridae Infections immunology, Sialic Acid Binding Ig-like Lectin 1 immunology, Toll-Like Receptor 7 immunology, Vesiculovirus physiology, Virus Replication immunology
- Abstract
Vesicular stomatitis virus (VSV) is an insect-transmitted rhabdovirus that is neurovirulent in mice. Upon peripheral VSV infection, CD169
+ subcapsular sinus (SCS) macrophages capture VSV in the lymph, support viral replication, and prevent CNS neuroinvasion. To date, the precise mechanisms controlling VSV infection in SCS macrophages remain incompletely understood. Here, we show that Toll-like receptor-7 (TLR7), the main sensing receptor for VSV, is central in controlling lymph-borne VSV infection. Following VSV skin infection, TLR7-/- mice display significantly less VSV titers in the draining lymph nodes (dLN) and viral replication is attenuated in SCS macrophages. In contrast to effects of TLR7 in impeding VSV replication in the dLN, TLR7-/- mice present elevated viral load in the brain and spinal cord highlighting their susceptibility to VSV neuroinvasion. By generating novel TLR7 floxed mice, we interrogate the impact of cell-specific TLR7 function in anti-viral immunity after VSV skin infection. Our data suggests that TLR7 signaling in SCS macrophages supports VSV replication in these cells, increasing LN infection and may account for the delayed onset of VSV-induced neurovirulence observed in TLR7-/- mice. Overall, we identify TLR7 as a novel and essential host factor that critically controls anti-viral immunity to VSV. Furthermore, the novel mouse model generated in our study will be of valuable importance to shed light on cell-intrinsic TLR7 biology in future studies.- Published
- 2019
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15. Sphingolipids in early viral replication and innate immune activation.
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Bezgovsek J, Gulbins E, Friedrich SK, Lang KS, and Duhan V
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- Animals, Hepatitis B virus growth & development, Hepatitis B virus immunology, Humans, Measles virus growth & development, Measles virus immunology, Orthomyxoviridae growth & development, Orthomyxoviridae immunology, Immunity, Innate immunology, Sphingolipids immunology, Sphingolipids metabolism, Virus Replication
- Abstract
In this review, we summarize the mechanisms by which sphingolipids modulate virus multiplication and the host innate immune response, using a number of host-virus systems as illustrative models. Sphingolipids exert diverse functions, both at the level of the viral life cycle and in the regulation of antiviral immune responses. Sphingolipids may influence viral replication in three ways: by serving as (co)receptors during viral entry, by modulating virus replication, and by shaping the antiviral immune response. Several studies have demonstrated that sphingosine kinases (SphK) and their product, sphingosine-1-phosphate (S1P), enhance the replication of influenza, measles, and hepatitis B virus (HBV). In contrast, ceramides, particularly S1P and SphK1, influence the expression of type I interferon (IFN-I) by modulating upstream antiviral signaling and enhancing dendritic cell maturation, differentiation, and positioning in tissue. The synthetic molecule α-galactosylceramide has also been shown to stimulate natural killer cell activation and interferon (IFN)-γ secretion. However, to date, clinical trials have failed to demonstrate any clinical benefit for sphingolipids in the treatment of cancer or HBV infection. Taken together, these findings show that sphingolipids play an important and underappreciated role in the control of virus replication and the innate immune response.
- Published
- 2018
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16. CEACAM1 promotes CD8 + T cell responses and improves control of a chronic viral infection.
- Author
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Khairnar V, Duhan V, Patil AM, Zhou F, Bhat H, Thoens C, Sharma P, Adomati T, Friendrich SK, Bezgovsek J, Dreesen JD, Wennemuth G, Westendorf AM, Zelinskyy G, Dittmer U, Hardt C, Timm J, Göthert JR, Lang PA, Singer BB, and Lang KS
- Subjects
- Adoptive Transfer, Animals, Bone Marrow Transplantation, CD8-Positive T-Lymphocytes metabolism, Carcinoembryonic Antigen genetics, Chimera, Chronic Disease, Female, Humans, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus pathogenicity, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Antigens, CD metabolism, CD8-Positive T-Lymphocytes immunology, Carcinoembryonic Antigen metabolism, Cell Adhesion Molecules metabolism, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology
- Abstract
Dysfunction of CD8
+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8+ T cells, and the absence of CEACAM1 on virus-specific CD8+ T cells limits the antiviral CD8+ T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8+ T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8+ T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus-specific CD8+ T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8+ T cells.- Published
- 2018
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17. Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity, and increased osteoclast activity.
- Author
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Wagner JM, Jaurich H, Wallner C, Abraham S, Becerikli M, Dadras M, Harati K, Duhan V, Khairnar V, Lehnhardt M, and Behr B
- Subjects
- Animals, B-Lymphocytes, Cell Differentiation, Cell Proliferation, Debridement, Female, Immunity, Innate, Male, Mice, Osteomyelitis immunology, Osteomyelitis surgery, Tumor Necrosis Factor-alpha metabolism, Wounds and Injuries complications, Bone Regeneration, Cytokines metabolism, Osteoblasts physiology, Osteoclasts physiology, Osteomyelitis metabolism
- Abstract
Osteomyelitis is a frequent consequence of open fractures thus representing a common bone infection with subsequent alteration of bone regeneration. Impaired bone homeostasis provokes serious variations in the bone remodeling process, thereby involving multiple inflammatory cytokines to activate bone healing. Our previously established mouse model of posttraumatic osteomyelitis provides the chance to study regulation of selected cytokines after surgical debridement of osteomyelitis thus illustrating the course of initial infectious recovery. An inflammatory cytokine array revealed specifically upregulated cytokines in debrided animals after bone infection, that were verified by Western blot analysis, identifying increased levels of CCL2, CCL3, and CXCL2. Increased osteoclastogenesis after debridement of osteomyelitis was demonstrated by Calcitonin-receptor and RANKL detection via immunohistochemical and -fluorescence stainings. The substantial protein analysis was complemented by uncovering diminished osteogenesis and proliferation in debrided group, tracking Osteocalcin, RUNX2, and PCNA expression. Interestingly TNF-α expression seemed to have no effect on altered bone regeneration after bone infection. Additional flow cytometry analysis proved elevated B cell activity, subsequently increased osteoclast activity and accelerated bone resorption. Based on the variety of severely altered cytokines, we propose a RANKL-dependent osteoclastogenesis after debridement of osteomyelitis coinciding with elevated B cells and simultaneously decreased osteogenesis. A comprehensive understanding of these mechanisms provides new therapeutic options of osteomyelitis cure and is of great importance in prospective medical treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2425-2434, 2017., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)
- Published
- 2017
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18. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury.
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Drommelschmidt K, Serdar M, Bendix I, Herz J, Bertling F, Prager S, Keller M, Ludwig AK, Duhan V, Radtke S, de Miroschedji K, Horn PA, van de Looij Y, Giebel B, and Felderhoff-Müser U
- Subjects
- Animals, Cognition physiology, Disease Models, Animal, Extracellular Vesicles metabolism, Mesenchymal Stem Cell Transplantation methods, Rats, Wistar, Brain Injuries metabolism, Encephalitis metabolism, Mesenchymal Stem Cells cytology, White Matter drug effects
- Abstract
Objective: Preterm brain injury is a major cause of disability in later life, and may result in motor, cognitive and behavioural impairment for which no treatment is currently available. The aetiology is considered as multifactorial, and one underlying key player is inflammation leading to white and grey matter injury. Extracellular vesicles secreted by mesenchymal stem/stromal cells (MSC-EVs) have shown therapeutic potential in regenerative medicine. Here, we investigated the effects of MSC-EV treatment on brain microstructure and maturation, inflammatory processes and long-time outcome in a rodent model of inflammation-induced brain injury., Methods: 3-Day-old Wistar rats (P3) were intraperitoneally injected with 0.25mg/kg lipopolysaccharide or saline and treated with two repetitive doses of 1×10
8 cell equivalents of MSC-EVs per kg bodyweight. Cellular degeneration and reactive gliosis at P5 and myelination at P11 were evaluated by immunohistochemistry and western blot. Long-term cognitive and motor function was assessed by behavioural testing. Diffusion tensor imaging at P125 evaluated long-term microstructural white matter alterations., Results: MSC-EV treatment significantly ameliorated inflammation-induced neuronal cellular degeneration reduced microgliosis and prevented reactive astrogliosis. Short-term myelination deficits and long-term microstructural abnormalities of the white matter were restored by MSC-EV administration. Morphological effects of MSC-EV treatment resulted in improved long-lasting cognitive functions INTERPRETATION: MSC-EVs ameliorate inflammation-induced cellular damage in a rat model of preterm brain injury. MSC-EVs may serve as a novel therapeutic option by prevention of neuronal cell death, restoration of white matter microstructure, reduction of gliosis and long-term functional improvement., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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19. CD169 + macrophages regulate PD-L1 expression via type I interferon and thereby prevent severe immunopathology after LCMV infection.
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Shaabani N, Duhan V, Khairnar V, Gassa A, Ferrer-Tur R, Häussinger D, Recher M, Zelinskyy G, Liu J, Dittmer U, Trilling M, Scheu S, Hardt C, Lang PA, Honke N, and Lang KS
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Chronic Disease, Cross-Priming immunology, Liver metabolism, Liver pathology, Liver virology, Lymph Nodes metabolism, Lymphocytic Choriomeningitis virology, Mice, Inbred C57BL, Spleen metabolism, B7-H1 Antigen metabolism, Interferon Type I metabolism, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis pathology, Lymphocytic choriomeningitis virus physiology, Macrophages metabolism, Sialic Acid Binding Ig-like Lectin 1 metabolism
- Abstract
Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and also upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8
+ T-cell exhaustion. How these very diverse functions are regulated remains unknown. This study, using the lymphocytic choriomeningitis virus, showed that a subset of CD169+ macrophages in murine spleen and lymph nodes produced high amounts of IFN-I upon infection. Absence of CD169+ macrophages led to insufficient production of IFN-I, lower antiviral activity and persistence of virus. Lack of CD169+ macrophages also limited the IFN-I-dependent expression of PD-L1. Enhanced viral replication in the absence of PD-L1 led to persistence of virus and prevented CD8+ T-cell exhaustion. As a consequence, mice exhibited severe immunopathology and died quickly after infection. Therefore, CD169+ macrophages are important contributors to the IFN-I response and thereby influence antiviral activity, CD8+ T-cell exhaustion and immunopathology.- Published
- 2016
- Full Text
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20. Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation.
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Shaabani N, Khairnar V, Duhan V, Zhou F, Tur RF, Häussinger D, Recher M, Tumanov AV, Hardt C, Pinschewer D, Christen U, Lang PA, Honke N, and Lang KS
- Subjects
- Animals, Disease Models, Animal, Humans, Interferon Type I biosynthesis, Lymph Nodes immunology, Lymph Nodes metabolism, Lymph Nodes virology, Lymphocyte Activation, Lymphocytes immunology, Lymphocytes metabolism, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus physiology, Lymphotoxin-beta metabolism, Macrophages immunology, Macrophages metabolism, Mice, Mice, Knockout, Spleen immunology, Spleen metabolism, Spleen virology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Adaptive Immunity, Immunity, Innate, Virus Replication immunology
- Abstract
The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18-dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8(+) T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell-derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8(+) T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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21. Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8(+) T-cell priming and viral control.
- Author
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Duhan V, Khairnar V, Friedrich SK, Zhou F, Gassa A, Honke N, Shaabani N, Gailus N, Botezatu L, Khandanpour C, Dittmer U, Häussinger D, Recher M, Hardt C, Lang PA, and Lang KS
- Subjects
- Animals, Antibodies, Viral genetics, Antibodies, Viral immunology, CD8-Positive T-Lymphocytes virology, Humans, Lymphocytic choriomeningitis virus immunology, Lymphoid Tissue immunology, Lymphoid Tissue virology, Mice, Spleen immunology, Spleen virology, Virus Diseases genetics, Virus Replication genetics, CD8-Positive T-Lymphocytes immunology, Lymphocytic choriomeningitis virus genetics, Virus Diseases immunology, Virus Replication immunology
- Abstract
Clinically used human vaccination aims to induce specific antibodies that can guarantee long-term protection against a pathogen. The reasons that other immune components often fail to induce protective immunity are still debated. Recently we found that enforced viral replication in secondary lymphoid organs is essential for immune activation. In this study we used the lymphocytic choriomeningitis virus (LCMV) to determine whether enforced virus replication occurs in the presence of virus-specific antibodies or virus-specific CD8(+) T cells. We found that after systemic recall infection with LCMV-WE the presence of virus-specific antibodies allowed intracellular replication of virus in the marginal zone of spleen. In contrast, specific antibodies limited viral replication in liver, lung, and kidney. Upon recall infection with the persistent virus strain LCMV-Docile, viral replication in spleen was essential for the priming of CD8(+) T cells and for viral control. In contrast to specific antibodies, memory CD8(+) T cells inhibited viral replication in marginal zone but failed to protect mice from persistent viral infection. We conclude that virus-specific antibodies limit viral infection in peripheral organs but still allow replication of LCMV in the marginal zone, a mechanism that allows immune boosting during recall infection and thereby guarantees control of persistent virus.
- Published
- 2016
- Full Text
- View/download PDF
22. High Frequencies of Anti-Host Reactive CD8+ T Cells Ignore Non-Hematopoietic Antigen after Bone Marrow Transplantation in a Murine Model.
- Author
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Gassa A, Kalkavan H, Jian F, Duhan V, Khairnar V, Shaabani N, Honke N, Carpinteiro A, Botezatu L, Crivello P, Dolff S, Ferencik S, Häussinger D, Khandanpour C, Fleischhauer K, Witzke O, Wahlers T, Hardt C, Lang PA, and Lang KS
- Subjects
- Alanine Transaminase metabolism, Animals, Antibodies immunology, Antigens, Viral genetics, Antigens, Viral immunology, Antigens, Viral metabolism, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Epitopes immunology, Flow Cytometry, Glycoproteins genetics, Glycoproteins immunology, Glycoproteins metabolism, Graft vs Host Disease etiology, Graft vs Host Disease metabolism, L-Lactate Dehydrogenase metabolism, Lipopolysaccharides toxicity, Lymphocytic choriomeningitis virus genetics, Lymphocytic choriomeningitis virus metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Animal, Peptide Fragments genetics, Peptide Fragments immunology, Peptide Fragments metabolism, Real-Time Polymerase Chain Reaction, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Transplantation, Homologous, Viral Proteins genetics, Viral Proteins immunology, Viral Proteins metabolism, Bone Marrow Transplantation, CD8-Positive T-Lymphocytes immunology, Immune Tolerance
- Abstract
Background: Graft versus host disease (GvHD) occurs in 20% of cases with patients having an MHC I matched bone marrow transplantation (BMT). Mechanisms causing this disease remain to be studied., Methods: Here we used a CD8+ T cell transgenic mouse line (P14/CD45.1+) and transgenic DEE mice bearing ubiquitously the glycoprotein 33-41 (GP33) antigen derived from the major lymphocytic choriomeningitis virus (LCMV) epitope to study mechanisms of tolerance in anti-host reactive CD8+ T cells after BMT., Results: We found that anti-host reactive CD8+ T cells (P14 T cells) were not negatively selected in the thymus and that they were present in wild type (WT) recipient mice as well as in DEE recipient mice. Anti-host reactive CD8+ T cells ignored the GP33 antigen expressed ubiquitously by host cells but they could be activated ex vivo via LCMV-infection. Lipopolysaccharides (LPS) induced transient cell damage in DEE mice bearing anti-host reactive CD8+ T cells after BMT, suggesting that induction of host inflammatory response could break antigen ignorance. Introducing the GP33 antigen into BM cells led to deletion of anti-host reactive CD8+ T cells., Conclusion: We found that after BMT anti-host reactive CD8+ T cells ignored host antigen in recipients and that they were only deleted when host antigen was present in hematopoietic cells. Moreover, LPS-induced immune activation contributed to induction of alloreactivity of anti-host reactive CD8+ T cells after BMT., (© 2016 S. Karger AG, Basel.)
- Published
- 2016
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23. IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts.
- Author
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Gassa A, Jian F, Kalkavan H, Duhan V, Honke N, Shaabani N, Friedrich SK, Dolff S, Wahlers T, Kribben A, Hardt C, Lang PA, Witzke O, and Lang KS
- Subjects
- Animals, Disease Models, Animal, Graft Rejection virology, Graft Survival, Immunization, Interleukin-10 genetics, Mice, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes metabolism, Graft Rejection prevention & control, Heart virology, Heart Transplantation adverse effects, Interleukin-10 metabolism, Lymphocytic choriomeningitis virus immunology
- Abstract
Background/aims: Unexpected transmissions of viral pathogens during solid organ transplantation (SOT) can result in severe, life-threatening diseases in transplant recipients. Immune activation contributes to disease onset. However mechanisms balancing the immune response against transmitted viral infection through organ transplantation remain unknown. Methods &, Results: Here we found, using lymphocytic choriomeningitis virus (LCMV), that transplantation of LCMV infected hearts led to exhaustion of virus specific CD8+ T cells, viral persistence in organs and survival of graft and recipient. Genetic depletion of Interleukin-10 (IL-10) resulted in strong immune activation, graft dysfunction and death of mice, suggesting that IL-10 was a major regulator of CD8+ T cell exhaustion during SOT. In the presence of memory CD8+ T cells, virus could be controlled. However sufficient antiviral immune response resulted in acute rejection of transplanted heart., Conclusion: We found that virus transmitted via SOT could not be controlled by naïve mice recipients due to IL-10 mediated CD8+ T cell exhaustion which thereby prevented immunopathology and graft failure whereas memory mice recipients were able to control the virus and induced graft failure., (© 2016 The Author(s) Published by S. Karger AG, Basel.)
- Published
- 2016
- Full Text
- View/download PDF
24. IFN-γ licenses CD11b(+) cells to induce progression of systemic lupus erythematosus.
- Author
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Shaabani N, Honke N, Dolff S, Görg B, Khairnar V, Merches K, Duhan V, Metzger S, Recher M, Barthuber C, Hardt C, Proksch P, Häussinger D, Witzke O, Lang PA, and Lang KS
- Subjects
- Animals, Autoantibodies immunology, Autoimmunity immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Disease Models, Animal, Disease Progression, Humans, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Lymphocyte Count, Mice, Mice, Knockout, Receptors, IgG genetics, Recurrence, CD11b Antigen metabolism, Interferon-gamma metabolism, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic metabolism, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism
- Abstract
Autoantibodies are a hallmark of autoimmune diseases, such as rheumatoid arthritis, autoimmune hepatitis, and systemic lupus erythematosus (SLE). High titers of anti-nuclear antibodies are used as surrogate marker for SLE, however their contribution to pathogenesis remains unclear. Using murine model of SLE and human samples, we studied the effect of immune stimulation on relapsing of SLE. Although autoantibodies bound to target cells in vivo, only additional activation of CD8(+) T cells converted this silent autoimmunity into overt disease. In mice as well as in humans CD8(+) T cells derived IFN-γ enhanced expression of Fc-receptors on CD11b(+) cells. High expression of Fc-receptors allowed CD11b(+) cells to bind to antibody covered target cells and to destroy them in vivo. We found that autoantibodies induce clinically relevant disease when adaptive immunity, specific for disease non-related antigen, is activated., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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25. Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.
- Author
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Xu HC, Huang J, Khairnar V, Duhan V, Pandyra AA, Grusdat M, Shinde P, McIlwain DR, Maney SK, Gommerman J, Löhning M, Ohashi PS, Mak TW, Pieper K, Sic H, Speletas M, Eibel H, Ware CF, Tumanov AV, Kruglov AA, Nedospasov SA, Häussinger D, Recher M, Lang KS, and Lang PA
- Subjects
- Adaptive Immunity, Animals, Immunity, Innate, Interferon Type I metabolism, Lymphocytic choriomeningitis virus immunology, Mice, Knockout, Signal Transduction, Vesiculovirus immunology, Arenaviridae Infections immunology, Macrophages chemistry, Macrophages immunology, Receptors, Interleukin-4 deficiency, Rhabdoviridae Infections immunology, Sialic Acid Binding Ig-like Lectin 1 analysis
- Abstract
Unlabelled: The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections., Importance: Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
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26. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production.
- Author
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Khairnar V, Duhan V, Maney SK, Honke N, Shaabani N, Pandyra AA, Seifert M, Pozdeev V, Xu HC, Sharma P, Baldin F, Marquardsen F, Merches K, Lang E, Kirschning C, Westendorf AM, Häussinger D, Lang F, Dittmer U, Küppers R, Recher M, Hardt C, Scheffrahn I, Beauchemin N, Göthert JR, Singer BB, Lang PA, and Lang KS
- Subjects
- Animals, Antibodies, Neutralizing immunology, B-Lymphocytes immunology, Bone Marrow metabolism, Bone Marrow Cells cytology, Cell Differentiation, Cell Proliferation, Cell Separation, Cell Survival, Flow Cytometry, Gene Expression Regulation, Immunoglobulin G immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Signal Transduction, Spleen metabolism, Vesiculovirus, Antibodies, Viral immunology, B-Lymphocytes cytology, Carcinoembryonic Antigen physiology
- Abstract
B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1(-/-) mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1(-/-) mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses.
- Published
- 2015
- Full Text
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27. Virus-Induced Type I Interferon Deteriorates Control of Systemic Pseudomonas Aeruginosa Infection.
- Author
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Merches K, Khairnar V, Knuschke T, Shaabani N, Honke N, Duhan V, Recher M, Navarini AA, Hardt C, Häussinger D, Tümmler B, Gulbins E, Futerman AH, Hoffmann D, Lang F, Lang PA, Westendorf AM, and Lang KS
- Subjects
- Animals, Granulocytes drug effects, Granulocytes metabolism, Immunity, Innate drug effects, Kupffer Cells drug effects, Kupffer Cells metabolism, Liver drug effects, Liver metabolism, Lymphocytic choriomeningitis virus drug effects, Mice, Inbred C57BL, Muramidase metabolism, Neutropenia immunology, Neutropenia pathology, Poly I-C pharmacology, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa pathogenicity, Spleen drug effects, Spleen metabolism, Virulence drug effects, Interferon Type I pharmacology, Lymphocytic choriomeningitis virus physiology, Pseudomonas Infections immunology, Pseudomonas Infections microbiology, Pseudomonas aeruginosa physiology
- Abstract
Background: Type I interferon (IFN-I) predisposes to bacterial superinfections, an important problem during viral infection or treatment with interferon-alpha (IFN-α). IFN-I-induced neutropenia is one reason for the impaired bacterial control; however there is evidence that more frequent bacterial infections during IFN-α-treatment occur independently of neutropenia., Methods: We analyzed in a mouse model, whether Pseudomonas aeruginosa control is influenced by co-infection with the lymphocytic choriomeningitis virus (LCMV). Bacterial titers, numbers of neutrophils and the gene-expression of liver-lysozyme-2 were determined during a 24 hours systemic infection with P. aeruginosa in wild-type and Ifnar(-/-) mice under the influence of LCMV or poly(I:C)., Results: Virus-induced IFN-I impaired the control of Pseudomonas aeruginosa. This was associated with neutropenia and loss of lysozyme-2-expression in the liver, which had captured P. aeruginosa. A lower release of IFN-I by poly(I:C)-injection also impaired the bacterial control in the liver and reduced the expression of liver-lysozyme-2. Low concentration of IFN-I after infection with a virulent strain of P. aeruginosa alone impaired the bacterial control and reduced lysozyme-2-expression in the liver as well., Conclusion: We found that during systemic infection with P. aeruginosa Kupffer cells quickly controlled the bacteria in cooperation with neutrophils. Upon LCMV-infection this cooperation was disturbed., (© 2015 S. Karger AG, Basel.)
- Published
- 2015
- Full Text
- View/download PDF
28. Protocol for long duration whole body hyperthermia in mice.
- Author
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Duhan V, Joshi N, Nagarajan P, and Upadhyay P
- Subjects
- Animals, Female, Mice, Mice, Inbred BALB C, Time Factors, Hyperthermia, Induced methods
- Abstract
Hyperthermia is a general term used to define the increase in core body temperature above normal. It is often used to describe the increased core body temperature that is observed during fever. The use of hyperthermia as an adjuvant has emerged as a promising procedure for tumor regression in the field of cancer biology. For this purpose, the most important requirement is to have reliable and uniform heating protocols. We have developed a protocol for hyperthermia (whole body) in mice. In this protocol, animals are exposed to cycles of hyperthermia for 90 min followed by a rest period of 15 min. During this period mice have easy access to food and water. High body temperature spikes in the mice during first few hyperthermia exposure cycles are prevented by immobilizing the animal. Additionally, normal saline is administered in first few cycles to minimize the effects of dehydration. This protocol can simulate fever like conditions in mice up to 12-24 hr. We have used 8-12 weeks old BALB/Cj female mice to demonstrate the protocol.
- Published
- 2012
- Full Text
- View/download PDF
29. Adjuvant properties of thermal component of hyperthermia enhanced transdermal immunization: effect on dendritic cells.
- Author
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Joshi N, Duhan V, Lingwal N, Bhaskar S, and Upadhyay P
- Subjects
- Administration, Cutaneous, Animals, Antigens, Neoplasm metabolism, Biomarkers metabolism, Bone Marrow Cells cytology, Cell Adhesion Molecules metabolism, Cell Differentiation drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Cytokines biosynthesis, Cytokines metabolism, Dendritic Cells cytology, Epidermal Cells, Epidermis drug effects, Epithelial Cell Adhesion Molecule, Fluoresceins metabolism, Immunization, Secondary, Immunologic Memory drug effects, Lymph Nodes cytology, Lymph Nodes drug effects, Lymphocyte Activation drug effects, Lymphocyte Culture Test, Mixed, Mice, Needles, Neutralization Tests, Succinimides metabolism, T-Lymphocytes cytology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Tetanus Toxoid toxicity, Up-Regulation drug effects, Adjuvants, Immunologic pharmacology, Dendritic Cells drug effects, Dendritic Cells immunology, Hyperthermia, Induced, Immunization
- Abstract
Hyperthermia enhanced transdermal (HET) immunization is a novel needle free immunization strategy employing application of antigen along with mild local hyperthermia (42°C) to intact skin resulting in detectable antigen specific Ig in serum. In the present study, we investigated the adjuvant effect of thermal component of HET immunization in terms of maturation of dendritic cells and its implication on the quality of the immune outcome in terms of antibody production upon HET immunization with tetanus toxoid (TT). We have shown that in vitro hyperthermia exposure at 42°C for 30 minutes up regulates the surface expression of maturation markers on bone marrow derived DCs. This observation correlated in vivo with an increased and accelerated expression of maturation markers on DCs in the draining lymph node upon HET immunization in mice. This effect was found to be independent of the antigen delivered and depends only on the thermal component of HET immunization. In vitro hyperthermia also led to enhanced capacity to stimulate CD4+ T cells in allo MLR and promotes the secretion of IL-10 by BMDCs, suggesting a potential for Th2 skewing of T cell response. HET immunization also induced a systemic T cell response to TT, as suggested by proliferation of splenocytes from immunized animal upon in vitro stimulation by TT. Exposure to heat during primary immunization led to generation of mainly IgG class of antibodies upon boosting, similar to the use of conventional alum adjuvant, thus highlighting the adjuvant potential of heat during HET immunization. Lastly, we have shown that mice immunized by tetanus toxoid using HET route exhibited protection against challenge with a lethal dose of tetanus toxin. Thus, in addition to being a painless, needle free delivery system it also has an immune modulatory potential.
- Published
- 2012
- Full Text
- View/download PDF
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