Richard Ciavarra - Academia.edu (original) (raw)

Papers by Richard Ciavarra

Research paper thumbnail of Early gene activation initiates neuroinflammation prior to VSV neuroinvasion: Impact on antiviral responses and sleep

Journal of neuroimmunology, Jan 15, 2017

Rapid eye movement (REM) sleep is rapidly and persistently suppressed during vesicular stomatitis... more Rapid eye movement (REM) sleep is rapidly and persistently suppressed during vesicular stomatitis virus (VSV) encephalitis in C57Bl/6J (B6) mice. REM sleep suppression was associated with a complex global brain chemokine/cytokine response with bimodal kinetics although regionally distinct cytokine profiles were readily identified. Cytokine mRNA was translated either immediately or suppressed until the pathogen was cleared from the CNS. Innate signaling pathway (TLRs, RIG-I) activation occurred rapidly and sequentially prior to VSV neuroinvasion suggesting that antiviral states are quickly established in the CNS in advance of viral pathogen penetration. Il1β suppressed REM sleep mimicking aspects of VSV-induced sleep alterations whereas some robustly induced chemokines may be protective of REM. Thus, multiple brain chemokines may mediate sleep across VSV encephalitis via differential somnogenic effects.

Research paper thumbnail of Role of peripheral immune response in microglia activation and regulation of brain chemokine and proinflammatory cytokine responses induced during VSV encephalitis

Journal of Neuroimmunology, 2014

We report herein that neuroinvasion by vesicular stomatitis virus (VSV) activates microglia and i... more We report herein that neuroinvasion by vesicular stomatitis virus (VSV) activates microglia and induces a peripheral dendritic cell (DC)-dependent inflammatory response in the central nervous system (CNS). VSV neuroinvasion rapidly induces multiple brain chemokine and proinflammatory cytokine mRNAs that display bimodal kinetics. Peripheral DC ablation or T cell depletion suppresses the second wave of this response demonstrating that infiltrating T cells are primarily responsible for the bimodal characteristics of this response. The robust infiltrate associated with VSV encephalitis likely depends on sustained production of brain CCL19 and CCR7 expression on infiltrating inflammatory cells.

Research paper thumbnail of Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Virology, 2009

Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central ... more Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45 high CD11b + ) and CD8 + T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8 + T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

Research paper thumbnail of Impact of macrophage and dendritic cell subset elimination on antiviral immunity, viral clearance and production of type 1 interferon

Virology, 2005

We report herein that vesicular stomatitis virus (VSV) induced a concurrent primary Th1 (T helper... more We report herein that vesicular stomatitis virus (VSV) induced a concurrent primary Th1 (T helper 1) and Th2 cytokine response detectable ex vivo. Liposome-encapsulated clodronate-mediated elimination of CD8À marginal dendritic cells (DCs) and splenic macrophages (mA), but not CD8+ interdigitating DCs, prior to infection resulted in a markedly diminished chemokine and Th1 (IL-2, interferon-g) cytokine response, although the Th2 response (IL-4) remained relatively intact. Repopulation with marginal DCs and marginal metallophilic macrophages (MMM) restored Th1 cytokine profiles but did not restore chemokine responsiveness or reduce VSV-induced morbidity/mortality. Chemokine competency returned approximately 4 weeks post-depletion, which correlated temporally with repopulation of the spleen with marginal zone macrophages (MZM) and red pulp macrophages (RPM). Unexpectedly, virus-induced morbidity persisted for over 1 month post-depletion and was associated with virus dissemination and distinctive histological lesions in the liver. Depletion of interferon-producing plasmacytoid dendritic cells did not account for virus-induced morbidity because serum levels of type I interferon were not diminished in Cl2MBP-liposomesome-treated mice. Thus, distinct mA subsets are critical for chemokine production and viral clearance, and, in their absence, VSV disseminates even in the presence of high titers of interferon. D

Research paper thumbnail of Jni 475110

Research paper thumbnail of Evaluation of Immunological Paradigms in a Virus Model: Are Dendritic Cells Critical for Antiviral Immunity and Viral Clearance?

The Journal of Immunology, 2006

We have examined the role of dendritic cells (DCs) in the antiviral immune response and viral cle... more We have examined the role of dendritic cells (DCs) in the antiviral immune response and viral clearance using a transgenic mouse model (CD11c-diphtheria toxin (DT) receptor GFP) that allows for their conditional ablation in vivo. DT administration systemically ablated conventional and IFN-producing plasmacytoid DCs (pDCs) in transgenic, but not nontransgenic littermates, without elimination of splenic macrophages. Unexpectedly, early (12 and 48 h postinfection) viral clearance of vesicular stomatitis virus was normal in DC-depleted mice despite markedly reduced serum titers of type I IFN. DC-depleted mice remained virus-free with the exception of a subset (ϳ30%) that developed overwhelming and fatal brain infections 6 days postinfection. However, DT treatment profoundly inhibited clonal expansion of naive CD8 ؉ vesicular stomatitis virus-specific T cells without altering the primary Th1 and Th2 cytokine response. Optimal clonal expansion required pDCs because selective elimination of these cells in vivo with a depleting Ab also suppressed expansion of tetramer ؉ cells, although Th1/Th2 cytokine production remained unaltered. Collectively, these data indicate that conventional DCs and to a lesser extent pDCs are critical for proliferation of naive antiviral T cells. However, other components of the primary adaptive immune response (Th1/Th2 cytokines) are essentially normal in the absence of DCs, which may account for the efficient viral clearance seen in DC-depleted mice. Thus, sufficient redundancy exists in the immune system to sustain efficient viral clearance despite loss of an APC considered essential for induction of a primary antiviral immune response.

Research paper thumbnail of Comparison of the lateral tail vein and the retro-orbital venous sinus as routes of intravenous drug delivery in a transgenic mouse model

Research paper thumbnail of Comparison of the lateral tail vein and the retro-orbital venous sinus as routes of intravenous drug delivery in a transgenic mouse model

Research paper thumbnail of Distinct macrophage subpopulations regulate viral encephalitis but not viral clearance in the CNS

Journal of Neuroimmunology, 2010

Intranasal application of vesicular stomatitis virus (VSV) induces acute encephalitis characteriz... more Intranasal application of vesicular stomatitis virus (VSV) induces acute encephalitis characterized by a pronounced myeloid and T cell infiltrate. The role of distinct phagocytic populations on VSV encephalitis was therefore examined in this study. Ablation of peripheral macrophages did not impair VSV encephalitis or viral clearance from the brain, whereas, depletion of splenic marginal dendritic cells impaired this response and enhanced morbidity/mortality. Selective depletion of brain perivascular macrophages also suppressed this response without altering viral clearance. Thus, two anatomically distinct phagocytic populations regulate VSV encephalitis in a non-redundant fashion although neither population is essential for viral clearance in the CNS.

Research paper thumbnail of Cytotoxic T Cells Specific for Antigens Expressed on Surface Immunoglobulin-P Ositive Cells

Research paper thumbnail of Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Virology, Apr 1, 2009

Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central ... more Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45 high CD11b + ) and CD8 + T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8 + T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

Research paper thumbnail of Influence of IgH V-region genes on the growth kinetics of a murine B cell leukemia (BCL1)

Journal of immunology (Baltimore, Md. : 1950), 1981

The growth kinetics of an IgM-bearing B cell leukemia of BALB/c (Ig-1a) origin, designated BCL1, ... more The growth kinetics of an IgM-bearing B cell leukemia of BALB/c (Ig-1a) origin, designated BCL1, has been investigated in 2 allotype immunoglobulin (Ig) heavy (H) chain congenic strains, C.B-20 (Ig-1b) and C.AL-20 (Ig-1d), and an (H) chain recombinant strain, BAB-14 (Ig-1a/1b), that carries Ig-1a genes in the variable (V)-region and Ig-1b genes in the constant (C)-region. When large numbers (10(6) to 10(7)) of BCL1 cells were injected into these mice, leukemia, as measured by the appearance of leukemic cells in peripheral blood with subsequent mortality, did not occur in C.B-20, was delayed in C.AL-20, and progressed at the same rate in BAB-14 relative to BALB/c control mice. These results indicate that an immune response directed against an antigen encoded for by an H chain V region gene (idiotype or variable-region allotype) or linked gene (minor histocompatibility antigen) prevents the growth of the BCL1 leukemia in the C.B-20 mice. Tumor resistance appears to be due to T cell ac...

Research paper thumbnail of Mechanisms for generating cell membrane antigens that are recognized by cytotoxic T lymphocytes

Federation proceedings, 1981

Studies with many viruses have revealed that viral specific protein synthesis is an obligatory st... more Studies with many viruses have revealed that viral specific protein synthesis is an obligatory step in generating antigens on target cells for antiviral cytotoxic T lymphocytes. This has been most clearly demonstrated with DI particles, virions that are structurally complete but lack infectious RNA. Adsorption of such particles onto target cell membranes does not render these cells susceptible to lytic attack by antiviral effector cells, unless some viral protein synthesis transpires. However, some viruses, such as Sendai virus, circumvent the requirement for viral protein synthesis via fusion of the viral envelope with the target cell membrane, a process mediated by a specialized fusion protein. Once inserted into the lipid bilayer, it is likely that viral components and self H-2 noncovalently associate so that the complex can be recognized by antiviral cytotoxic T cells. This idea is supported by the demonstration that viral proteins and H-2 containing membrane proteins, incorpora...

Research paper thumbnail of Vesicular stomatitis antigens recognized by cytotoxic cells: analysis with defective interfering particles and reconstituted membrane vesicles

Journal of immunology (Baltimore, Md. : 1950), 1980

... RICHARD P. CIAVARRA, C. YONG KANG, AND JAMES FORMAN From the Department of Microbiology, Univ... more ... RICHARD P. CIAVARRA, C. YONG KANG, AND JAMES FORMAN From the Department of Microbiology, University of Texas Health Science Center at Dallas, 5323 Harry Hines Blud., Dallas, Texas 75235 ... This issue has recently been addressed by Henney (10). ...

Research paper thumbnail of Cells treated with trinitrobenzene sulfonic acid express an antigenic determinant recognized by cytotoxic effector cells that is not detected on cells coated with trinitrophenylated proteins

Journal of immunology (Baltimore, Md. : 1950), 1980

ABSTRACT Spleen cells cultured with TNBS-treated stimulator cells or TNP-HGG generate H-2 restric... more ABSTRACT Spleen cells cultured with TNBS-treated stimulator cells or TNP-HGG generate H-2 restricted anti-TNP cytotoxic effector cells. Antigenic determinants recognized by anti-TNP effector cells were analyzed by a cold target competition assay. Three major observations emerged from these studies: 1) Anti-TNP effector cells sensitized against 1 mM TNBS-treated stimulator cells are blocked from killing TNBS-treated target cells by unlabeled TNBS-inhibitor cells but not inhibitor cells coated with TNP-HGG. However, the same effector cells are blocked from killing TNP-HGG-coated target cells by inhibitor cells treated either with TNBS or coated with TNP-HGG. 2) Inhibitor cells exposed to a low concentration of TNBS (0.01 mM) block effector cell activity in a manner similar to TNP-HGG-coated inhibitors. 3) Spleen cells sensitized against TNP-HGG are blocked from killing TNBS-treated target cells by both TNBS-treated and TNP-HGG-inhibitor cells. These results indicate that spleen cells sensitized against TNBS-treated stimulators generate effector cells against two different antigenic specificities; one is immunodominant and (1 mM) TNBS dependent, the second is not. Target cells treated with low concentrations of TNBS (0.01 mM) or coated with TNP-HGG express only the second determinant. It is possible that the (1 mM) TNBS-dependent immunodominant determinant represents TNP covalently coupled to H-2, whereas the second determinant consists of TNP-proteins noncovalently associated with H-2 molecules and may represent a cross-reaction with environmental antigens.

Research paper thumbnail of Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Virology, 2009

Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central ... more Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45 high CD11b + ) and CD8 + T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8 + T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

Research paper thumbnail of H-2L-restricted recognition of viral antigens In the H-2d haplotype, anti-vesicular stomatitis virus cytotoxic T cells are restricted solely by H-2L

Journal of Experimental Medicine, 1982

Research paper thumbnail of A simplified procedure for the preparation of Sephadex G-200 for the separation of rat serum IgG and IgM

Journal of Chromatography A, 1971

Research paper thumbnail of Immune rejection mechanisms in murine leukemia. I. Timing of tumor cell rejection process relative to the development of humoral and cell-mediated cytotoxic immune responses

International Journal of Cancer, 1984

Studies were undertaken to investigate the relationship between cell-mediated and humoral immune ... more Studies were undertaken to investigate the relationship between cell-mediated and humoral immune responses in the rejection of LIZIOIMTX-Rev (LR) leukemia cells in CDZF, mice. The anti-LRantibudy (humoral) response was defined by both ik cytotoxic antibody titer and isotype composition, assessed by a complement-dependent cytotoxicity assay and radioimmune assay, respectively. The cytotoxic thymus m d e r i v e d lymphocyte response in the

Research paper thumbnail of Cell Membrane Antigens Recognized by Anti-Viral and Anti-Trinitrophenyl Cytotoxic T Lymphocytes

Immunological Reviews, 1981

Research paper thumbnail of Early gene activation initiates neuroinflammation prior to VSV neuroinvasion: Impact on antiviral responses and sleep

Journal of neuroimmunology, Jan 15, 2017

Rapid eye movement (REM) sleep is rapidly and persistently suppressed during vesicular stomatitis... more Rapid eye movement (REM) sleep is rapidly and persistently suppressed during vesicular stomatitis virus (VSV) encephalitis in C57Bl/6J (B6) mice. REM sleep suppression was associated with a complex global brain chemokine/cytokine response with bimodal kinetics although regionally distinct cytokine profiles were readily identified. Cytokine mRNA was translated either immediately or suppressed until the pathogen was cleared from the CNS. Innate signaling pathway (TLRs, RIG-I) activation occurred rapidly and sequentially prior to VSV neuroinvasion suggesting that antiviral states are quickly established in the CNS in advance of viral pathogen penetration. Il1β suppressed REM sleep mimicking aspects of VSV-induced sleep alterations whereas some robustly induced chemokines may be protective of REM. Thus, multiple brain chemokines may mediate sleep across VSV encephalitis via differential somnogenic effects.

Research paper thumbnail of Role of peripheral immune response in microglia activation and regulation of brain chemokine and proinflammatory cytokine responses induced during VSV encephalitis

Journal of Neuroimmunology, 2014

We report herein that neuroinvasion by vesicular stomatitis virus (VSV) activates microglia and i... more We report herein that neuroinvasion by vesicular stomatitis virus (VSV) activates microglia and induces a peripheral dendritic cell (DC)-dependent inflammatory response in the central nervous system (CNS). VSV neuroinvasion rapidly induces multiple brain chemokine and proinflammatory cytokine mRNAs that display bimodal kinetics. Peripheral DC ablation or T cell depletion suppresses the second wave of this response demonstrating that infiltrating T cells are primarily responsible for the bimodal characteristics of this response. The robust infiltrate associated with VSV encephalitis likely depends on sustained production of brain CCL19 and CCR7 expression on infiltrating inflammatory cells.

Research paper thumbnail of Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Virology, 2009

Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central ... more Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45 high CD11b + ) and CD8 + T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8 + T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

Research paper thumbnail of Impact of macrophage and dendritic cell subset elimination on antiviral immunity, viral clearance and production of type 1 interferon

Virology, 2005

We report herein that vesicular stomatitis virus (VSV) induced a concurrent primary Th1 (T helper... more We report herein that vesicular stomatitis virus (VSV) induced a concurrent primary Th1 (T helper 1) and Th2 cytokine response detectable ex vivo. Liposome-encapsulated clodronate-mediated elimination of CD8À marginal dendritic cells (DCs) and splenic macrophages (mA), but not CD8+ interdigitating DCs, prior to infection resulted in a markedly diminished chemokine and Th1 (IL-2, interferon-g) cytokine response, although the Th2 response (IL-4) remained relatively intact. Repopulation with marginal DCs and marginal metallophilic macrophages (MMM) restored Th1 cytokine profiles but did not restore chemokine responsiveness or reduce VSV-induced morbidity/mortality. Chemokine competency returned approximately 4 weeks post-depletion, which correlated temporally with repopulation of the spleen with marginal zone macrophages (MZM) and red pulp macrophages (RPM). Unexpectedly, virus-induced morbidity persisted for over 1 month post-depletion and was associated with virus dissemination and distinctive histological lesions in the liver. Depletion of interferon-producing plasmacytoid dendritic cells did not account for virus-induced morbidity because serum levels of type I interferon were not diminished in Cl2MBP-liposomesome-treated mice. Thus, distinct mA subsets are critical for chemokine production and viral clearance, and, in their absence, VSV disseminates even in the presence of high titers of interferon. D

Research paper thumbnail of Jni 475110

Research paper thumbnail of Evaluation of Immunological Paradigms in a Virus Model: Are Dendritic Cells Critical for Antiviral Immunity and Viral Clearance?

The Journal of Immunology, 2006

We have examined the role of dendritic cells (DCs) in the antiviral immune response and viral cle... more We have examined the role of dendritic cells (DCs) in the antiviral immune response and viral clearance using a transgenic mouse model (CD11c-diphtheria toxin (DT) receptor GFP) that allows for their conditional ablation in vivo. DT administration systemically ablated conventional and IFN-producing plasmacytoid DCs (pDCs) in transgenic, but not nontransgenic littermates, without elimination of splenic macrophages. Unexpectedly, early (12 and 48 h postinfection) viral clearance of vesicular stomatitis virus was normal in DC-depleted mice despite markedly reduced serum titers of type I IFN. DC-depleted mice remained virus-free with the exception of a subset (ϳ30%) that developed overwhelming and fatal brain infections 6 days postinfection. However, DT treatment profoundly inhibited clonal expansion of naive CD8 ؉ vesicular stomatitis virus-specific T cells without altering the primary Th1 and Th2 cytokine response. Optimal clonal expansion required pDCs because selective elimination of these cells in vivo with a depleting Ab also suppressed expansion of tetramer ؉ cells, although Th1/Th2 cytokine production remained unaltered. Collectively, these data indicate that conventional DCs and to a lesser extent pDCs are critical for proliferation of naive antiviral T cells. However, other components of the primary adaptive immune response (Th1/Th2 cytokines) are essentially normal in the absence of DCs, which may account for the efficient viral clearance seen in DC-depleted mice. Thus, sufficient redundancy exists in the immune system to sustain efficient viral clearance despite loss of an APC considered essential for induction of a primary antiviral immune response.

Research paper thumbnail of Comparison of the lateral tail vein and the retro-orbital venous sinus as routes of intravenous drug delivery in a transgenic mouse model

Research paper thumbnail of Comparison of the lateral tail vein and the retro-orbital venous sinus as routes of intravenous drug delivery in a transgenic mouse model

Research paper thumbnail of Distinct macrophage subpopulations regulate viral encephalitis but not viral clearance in the CNS

Journal of Neuroimmunology, 2010

Intranasal application of vesicular stomatitis virus (VSV) induces acute encephalitis characteriz... more Intranasal application of vesicular stomatitis virus (VSV) induces acute encephalitis characterized by a pronounced myeloid and T cell infiltrate. The role of distinct phagocytic populations on VSV encephalitis was therefore examined in this study. Ablation of peripheral macrophages did not impair VSV encephalitis or viral clearance from the brain, whereas, depletion of splenic marginal dendritic cells impaired this response and enhanced morbidity/mortality. Selective depletion of brain perivascular macrophages also suppressed this response without altering viral clearance. Thus, two anatomically distinct phagocytic populations regulate VSV encephalitis in a non-redundant fashion although neither population is essential for viral clearance in the CNS.

Research paper thumbnail of Cytotoxic T Cells Specific for Antigens Expressed on Surface Immunoglobulin-P Ositive Cells

Research paper thumbnail of Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Virology, Apr 1, 2009

Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central ... more Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45 high CD11b + ) and CD8 + T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8 + T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

Research paper thumbnail of Influence of IgH V-region genes on the growth kinetics of a murine B cell leukemia (BCL1)

Journal of immunology (Baltimore, Md. : 1950), 1981

The growth kinetics of an IgM-bearing B cell leukemia of BALB/c (Ig-1a) origin, designated BCL1, ... more The growth kinetics of an IgM-bearing B cell leukemia of BALB/c (Ig-1a) origin, designated BCL1, has been investigated in 2 allotype immunoglobulin (Ig) heavy (H) chain congenic strains, C.B-20 (Ig-1b) and C.AL-20 (Ig-1d), and an (H) chain recombinant strain, BAB-14 (Ig-1a/1b), that carries Ig-1a genes in the variable (V)-region and Ig-1b genes in the constant (C)-region. When large numbers (10(6) to 10(7)) of BCL1 cells were injected into these mice, leukemia, as measured by the appearance of leukemic cells in peripheral blood with subsequent mortality, did not occur in C.B-20, was delayed in C.AL-20, and progressed at the same rate in BAB-14 relative to BALB/c control mice. These results indicate that an immune response directed against an antigen encoded for by an H chain V region gene (idiotype or variable-region allotype) or linked gene (minor histocompatibility antigen) prevents the growth of the BCL1 leukemia in the C.B-20 mice. Tumor resistance appears to be due to T cell ac...

Research paper thumbnail of Mechanisms for generating cell membrane antigens that are recognized by cytotoxic T lymphocytes

Federation proceedings, 1981

Studies with many viruses have revealed that viral specific protein synthesis is an obligatory st... more Studies with many viruses have revealed that viral specific protein synthesis is an obligatory step in generating antigens on target cells for antiviral cytotoxic T lymphocytes. This has been most clearly demonstrated with DI particles, virions that are structurally complete but lack infectious RNA. Adsorption of such particles onto target cell membranes does not render these cells susceptible to lytic attack by antiviral effector cells, unless some viral protein synthesis transpires. However, some viruses, such as Sendai virus, circumvent the requirement for viral protein synthesis via fusion of the viral envelope with the target cell membrane, a process mediated by a specialized fusion protein. Once inserted into the lipid bilayer, it is likely that viral components and self H-2 noncovalently associate so that the complex can be recognized by antiviral cytotoxic T cells. This idea is supported by the demonstration that viral proteins and H-2 containing membrane proteins, incorpora...

Research paper thumbnail of Vesicular stomatitis antigens recognized by cytotoxic cells: analysis with defective interfering particles and reconstituted membrane vesicles

Journal of immunology (Baltimore, Md. : 1950), 1980

... RICHARD P. CIAVARRA, C. YONG KANG, AND JAMES FORMAN From the Department of Microbiology, Univ... more ... RICHARD P. CIAVARRA, C. YONG KANG, AND JAMES FORMAN From the Department of Microbiology, University of Texas Health Science Center at Dallas, 5323 Harry Hines Blud., Dallas, Texas 75235 ... This issue has recently been addressed by Henney (10). ...

Research paper thumbnail of Cells treated with trinitrobenzene sulfonic acid express an antigenic determinant recognized by cytotoxic effector cells that is not detected on cells coated with trinitrophenylated proteins

Journal of immunology (Baltimore, Md. : 1950), 1980

ABSTRACT Spleen cells cultured with TNBS-treated stimulator cells or TNP-HGG generate H-2 restric... more ABSTRACT Spleen cells cultured with TNBS-treated stimulator cells or TNP-HGG generate H-2 restricted anti-TNP cytotoxic effector cells. Antigenic determinants recognized by anti-TNP effector cells were analyzed by a cold target competition assay. Three major observations emerged from these studies: 1) Anti-TNP effector cells sensitized against 1 mM TNBS-treated stimulator cells are blocked from killing TNBS-treated target cells by unlabeled TNBS-inhibitor cells but not inhibitor cells coated with TNP-HGG. However, the same effector cells are blocked from killing TNP-HGG-coated target cells by inhibitor cells treated either with TNBS or coated with TNP-HGG. 2) Inhibitor cells exposed to a low concentration of TNBS (0.01 mM) block effector cell activity in a manner similar to TNP-HGG-coated inhibitors. 3) Spleen cells sensitized against TNP-HGG are blocked from killing TNBS-treated target cells by both TNBS-treated and TNP-HGG-inhibitor cells. These results indicate that spleen cells sensitized against TNBS-treated stimulators generate effector cells against two different antigenic specificities; one is immunodominant and (1 mM) TNBS dependent, the second is not. Target cells treated with low concentrations of TNBS (0.01 mM) or coated with TNP-HGG express only the second determinant. It is possible that the (1 mM) TNBS-dependent immunodominant determinant represents TNP covalently coupled to H-2, whereas the second determinant consists of TNP-proteins noncovalently associated with H-2 molecules and may represent a cross-reaction with environmental antigens.

Research paper thumbnail of Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

Virology, 2009

Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central ... more Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45 high CD11b + ) and CD8 + T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8 + T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

Research paper thumbnail of H-2L-restricted recognition of viral antigens In the H-2d haplotype, anti-vesicular stomatitis virus cytotoxic T cells are restricted solely by H-2L

Journal of Experimental Medicine, 1982

Research paper thumbnail of A simplified procedure for the preparation of Sephadex G-200 for the separation of rat serum IgG and IgM

Journal of Chromatography A, 1971

Research paper thumbnail of Immune rejection mechanisms in murine leukemia. I. Timing of tumor cell rejection process relative to the development of humoral and cell-mediated cytotoxic immune responses

International Journal of Cancer, 1984

Studies were undertaken to investigate the relationship between cell-mediated and humoral immune ... more Studies were undertaken to investigate the relationship between cell-mediated and humoral immune responses in the rejection of LIZIOIMTX-Rev (LR) leukemia cells in CDZF, mice. The anti-LRantibudy (humoral) response was defined by both ik cytotoxic antibody titer and isotype composition, assessed by a complement-dependent cytotoxicity assay and radioimmune assay, respectively. The cytotoxic thymus m d e r i v e d lymphocyte response in the

Research paper thumbnail of Cell Membrane Antigens Recognized by Anti-Viral and Anti-Trinitrophenyl Cytotoxic T Lymphocytes

Immunological Reviews, 1981