| 1. |
- Eriksson, Kristina, 1962, et al.
(författare)
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Coupling of antigen to cholera toxin for dendritic cell vaccination promotes the induction of MHC class I-restricted cytotoxic T cells and the rejection of a cognate antigen-expressing model tumor.
- 2004
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 34:5, s. 1272-81
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Tidskriftsartikel (refereegranskat)abstract
- We previously demonstrated that cholera toxin (CT) is highly efficient as a combined carrier and adjuvant for dendritic cell (DC) vaccination, inducing strong Th1-dominated B cell and CD4(+) T cell responses. In this study we show that vaccination with DC pre-pulsed ex vivo with CT-conjugated OVA (OVA-CT) gives rise to OVA-specific CD8(+) T cells that produce IFN-gamma and are cytotoxic for OVA-expressing E.G7 tumor cells both in vitro and in vivo. The induction of specific CD8(+) CTL by OVA-CT-treated DC was associated with enhanced presentation of OVA peptide (SIINFEKL) on MHC class I in combination with an overall activation of the pulsed DC. Vaccination of mice with OVA-CT-pulsed DC resulted in rejection of already established MHC class I-positive, MHC class II-negative, OVA-expressing E.G7 tumors in an antigen-specific, CD8(+) T cell-dependent fashion and was associated with high numbers of tumor-infiltrating CD8(+) T cells. Conjugation of antigen to CT facilitated DC uptake of the linked antigen through the GM1 receptor-binding B subunit and induced strong activation-maturation signals through the biologically active A subunit. These results have interesting implications for DC vaccination aimed at inducing CTL immune responses.
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| 2. |
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| 3. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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Vaccination with dendritic cells pulsed in vitro with tumor antigen conjugated to cholera toxin efficiently induces specific tumoricidal CD8+ cytotoxic lymphocytes dependent on cyclic AMP activation of dendritic cells.
- 2004
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Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 112:1, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the development of CD8+ tumor-specific cytotoxic lymphocytes (CTL) and protection against tumor growth after vaccination with bone marrow-derived dendritic cells (DC) pulsed with a model protein ovalbumin conjugated to cholera toxin (OVA-CT) in B6 mice using E.G7 tumor cells expressing OVA(257-264) peptide (SIINFEKL) as target cells in vitro and in vivo. Vaccination with OVA-CT-pulsed DC concurrently induced strong CTL in vitro activity and anti-E.G7 tumor protection in vivo in WT, NK-depleted and CD4-deficient mice as well as in IL-12-/- and IFN-gamma-/- mice but not in CD8-deficient mice. Importantly, activation of CTL by OVA-CT-pulsed DC was dependent on CT-induced activation of adenylate cyclase and increased cAMP production by DC associated with increased expression of MHC class I and co-stimulatory molecules (CD80, CD86 and CD40). These results show that vaccination with DC pulsed with antigens (Ag) conjugated to CT induces a strong CTL response and suggest that conjugation of tumor Ag to CT for DC vaccination represents a promising approach for tumor vaccination and immunotherapy.
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| 4. |
- Cuburu, Nicolas, et al.
(författare)
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Sublingual immunization induces broad-based systemic and mucosal immune responses in mice.
- 2007
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 25:51, s. 8598-610
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The potential of sublingual (s.l.) delivery of vaccine was examined in mice. We show the existence of a dense network of dendritic cells (DCs) in the s.l. epithelium and a rapid and transient increase in the frequency of s.l. DCs after topical application of cholera toxin (CT) adjuvant under the tongue. S.l. immunization with ovalbumin and CT induced vigorous systemic and mucosal antibody responses. Such treatment promoted mixed Th1 and Th2 cytokine responses and induced cytotoxic CD8(+) T cells in lung tissues and in systemic lymphoid organs. S.l. immunization was comparable to intranasal immunization and was superior to oral immunization regarding the magnitude and anatomic dissemination of the induced immune responses. S.l. administration of live influenza virus at a dose lethal by the nasal route was well tolerated and did not redirect virus to the olfactory bulb. These features underscore the potential of the s.l. mucosa to serve as an alternative vaccine delivery route.
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| 5. |
- Holmgren, Jan, 1944, et al.
(författare)
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Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA
- 2005
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Ingår i: Immunology Letters. - : Elsevier. - 0165-2478 .- 1879-0542. ; 97:2, s. 181-8
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal immunisation may be used both to protect the mucosal surfaces against infections and as a means for immunological treatment of peripheral immunopathological disorders through the induction of systemic antigen-specific tolerance ('oral tolerance'). The development of mucosal vaccines, whether for prevention of infectious diseases or for oral tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems that can help to present the appropriate vaccine or immunotherapy antigens to the mucosal immune system. The most potent (but also toxic) mucosal adjuvants are cholera toxin (CT) and the closely related Escherichia coli heat-labile enterotoxin (LT), and much effort and significant progress have been made recently to generate toxicologically acceptable derivatives of these toxins with retained adjuvant activity. Among these are the non-toxic, recombinantly produced cholera toxin B-subunit (CTB). CTB is a specific protective antigen component of a widely registered oral cholera vaccine as well as a promising vector for either giving rise to mucosal anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. CT and CTB have also recently been used as combined vectors and adjuvants for markedly promoting ex vivo dendritic cell (DC) vaccination with different antigens and also steering the immune response to the in vivo-reinfused DCs towards either broad Th1 + Th2 + CTL immunity (CT) or Th2 or tolerance (CTB). Another type of mucosal adjuvants is represented by bacterial DNA or synthetic oligodeoxynucleotides containing CpG-motifs, which especially when linked to CTB have been found to effectively stimulate both innate and adaptive mucosal immune responses. The properties and clinical potential of these different classes of adjuvants are being discussed. © 2004 Elsevier B.V. All rights reserved.
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| 6. |
- Lindgren, Åsa, 1979, et al.
(författare)
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Impaired IFN-gamma Production after Stimulation with Bacterial Components by Natural Killer Cells from Gastric Cancer Patients
- 2011
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 317:6, s. 849-858
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Tidskriftsartikel (refereegranskat)abstract
- Gastric adenocarcinoma is a major health problem world-wide, as this is the second most common cause of cancer death in the world. It has been estimated that infection by Helicobacter pylori cause at least half of the gastric cancers. Previously, we have demonstrated that H. pylori antigens directly activate NK cells to secrete IFN-γ. There is also a marked synergistic effect in NK cells stimulated with bacterial lysate and low levels of IL-12, a cytokine which is produced by macrophages and dendritic cells in the H. pylori-infected stomach. The present study was designed to investigate whether NK cells from gastric cancer patients display an altered ability to respond to components from H. pylori and other bacteria. The results show that NK cells from peripheral blood of gastric cancer patients have a severely suppressed ability to produce IFN-γ after stimulation with H. pylori lysate and the synthetic bacterial lipoprotein FSL-1. Furthermore, the synergistic effect of IL-12 and lysate is absent in gastric cancer patients, unless the concentration of IL-12 is increased 10-fold. We also demonstrate that there is a similar lack of IFN-γ production from NK cells isolated from the gastric mucosa of cancer patients. In addition, we propose that the observed suppression is due to tumour-derived TGF-β and that increased expression of the transcription factor GATA-3 may be responsible for the TGF-β induced suppression.
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| 7. |
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| 8. |
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| 9. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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B lymphocytes promote expansion of regulatory T cells in oral tolerance: powerful induction by antigen coupled to cholera toxin B subunit.
- 2008
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 1550-6606. ; 181:12, s. 8278-87
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal administration of Ag conjugated to cholera toxin B subunit (CTB) can efficiently induce peripheral immunologic tolerance, so-called oral tolerance, associated with development of Foxp3(+)CD25(+)CD4(+) regulatory T (Treg) cells. Using an established sublingual tolerization regimen with Ag(OVA)/CTB conjugate, wherein CTB mediates Ag uptake and presentation by most B lymphocytes irrespective of their Ag specificity, we have assessed the importance of B cells for induction of Ag-specific Treg cells and oral tolerance. We found that Treg cells are reduced in microMT(-/-) B cell-deficient mice compared with wild-type (WT) mice. After sublingual Ag/CTB treatment, Treg cells increased much more in WT than in microMT(-/-) mice; however, adoptive transfer of B cells before treatment normalized Treg cell development and functional oral tolerance. B cells from OVA/CTB-treated mice expressed more IL-10 and less CD86 than control B cells. Adoptive transfer of these cells before parenteral immunization with OVA led to efficient suppression of proliferation and to induction of apoptotic depletion of Ag-specific CD25(-)CD4(+) effector T cells associated with the expansion of Treg cells. However, also OVA/CTB-treated microMT(-/-) mice could suppress the immune response to parenteral immunization with OVA, which was associated with a strong increase in Foxp3(-)CD4(+) T cells expressing LAP/TGF-beta. Our results indicate that mucosal tolerance comprises at least two separate pathways: one being B cell dependent and associated with expansion of Treg cells and Treg-mediated suppression and depletion of effector T cells, and one being B cell independent and associated with development of Foxp3(-)LAP(+)TGF-beta(+) regulatory T cells.
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| 10. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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B lymphocytes treated in vitro with antigen coupled to cholera toxin B subunit induce antigen-specific Foxp3(+) regulatory T cells and protect against experimental autoimmune encephalomyelitis.
- 2012
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 188:4, s. 1686-1697
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Tidskriftsartikel (refereegranskat)abstract
- The ability of activated B cells to protect against various experimental autoimmune or allergic diseases makes them attractive for use in cell-based therapies. We describe an efficient way to generate B cells with strong suppressive functions by incubating naive B cells with a relevant Ag conjugated to cholera toxin B subunit (CTB). This allows most B cells, irrespective of BCR, to take up and present Ag and induces their expression of latency-associated polypeptide (LAP)/TGF-β and after adoptive transfer also their production of IL-10. With OVA as model Ag, when naive T cells were cocultured in vitro with B cells pretreated with OVA conjugated to CTB (OVA/CTB) Ag-specific CD4(+) Foxp3 regulatory T (Treg) cells increased >50-fold. These cells effectively suppressed CD25(-)CD4(+) effector T (Teff) cells in secondary cultures. Adoptive transfer of OVA/CTB-treated B cells to mice subsequently immunized with OVA in CFA induced increase in Foxp3 Treg cells together with suppression and depletion of Teff cells. Likewise, adoptive transfer of B cells pulsed with myelin oligodendrocyte glycoprotein peptide(35-55) (MOGp) conjugated to CTB increased the number of Treg cells, suppressed MOGp-specific T cell proliferation and IL-17 and IFN-γ production, and prevented the development of experimental autoimmune encephalomyelitis. Similar effects were seen when B cells were given "therapeutically" to mice with early-stage experimental autoimmune encephalomyelitis. Our results suggest that B cells pulsed in vitro with relevant Ag/CTB conjugates may be used in cell therapy to induce Ag-specific suppression of autoimmune disease.
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| 11. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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Important Role for Fc gamma RIIB on B Lymphocytes for Mucosal Antigen-Induced Tolerance and Foxp3(+) Regulatory T Cells
- 2013
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 191:8, s. 4412-4422
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Tidskriftsartikel (refereegranskat)abstract
- Fc gamma RIIB, the only Fc gamma R expressed on B cells, is important in the maintenance of immunological tolerance to self-Ags. In this study, we investigated the role of Fc gamma RIIB in Ag-specific CD4 T cell tolerance induced by mucosally administered Ag (OVA) coupled to cholera toxin B subunit (Ag/CTB) or given alone. We found that sublingual administration of Ag/CTB conjugate or intragastric administration of a >100-fold higher dose of Ag alone efficiently suppressed parenteral immunization-induced Ag-specific T cell proliferation and delayed-type hypersensitivity responses in Fc gamma RIIB-expressing wild-type (WT), but not Fc gamma RIIB-/-, mice. Such mucosally induced tolerance (oral tolerance) associated with induction of Ag-specific Foxp3(+) regulatory T cells was restored in Fc gamma RIIB-/- mice by adoptive transfer of either WT B cells or WT dendritic cells before the mucosal Ag/CTB treatment; it was even more pronounced in mu MT mice that received Fc gamma RIIB-overexpressing B cells before treatment. Furthermore, cell transfer in either WT or mu MT mice of WT but not Fc gamma RIIB-/- B cells pretreated for 1 h in vitro with Ag/CTB conjugate induced Ag-specific immunological tolerance, which was further enhanced by adoptive transfer of WT B cells pretreated with anti-Ag IgG immune complexed Ag/CTB. We conclude that Fc gamma RIIB expression on B cells, in addition to dendritic cells, is important for mucosal induction of Ag-specific immune tolerance.
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| 12. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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Lack of Fc Gamma Receptor IIIA Promotes Rather than Suppresses Humoral and Cellular Immune Responses after Mucosal or Parenteral Immunization with Antigen and Adjuvants
- 2017
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 85:4, s. 264-271
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Tidskriftsartikel (refereegranskat)abstract
- The Fcc receptor IIIA (Fc gamma RIIIA) has traditionally been known as a positive regulator of immune responses. Consistent with this, mice deficient in Fc gamma RIIIA are protected from various inflammation-associated pathologies including several autoimmune diseases. In contrast to this accepted dogma, we show here that mice lacking Fc gamma RIIIA developed increased rather than reduced both humoral and cellular immune responses to mucosal (sublingual) immunization with ovalbumin (OVA) given together with the strong mucosal adjuvant cholera toxin as well as to parenteral (subcutaneous) immunization with OVA in complete Freund's adjuvant. After either route of immunization, in comparison with concomitantly immunized wild-type mice, Fc gamma RIIIA(-/)-mice had increased serum anti-OVA IgG (IgG1 but not IgG2) antibody responses as well as augmented cellular responses that included memory B cells and effector T cells. The increments in immune responses in Fc gamma RIIIA(-/)-mice were similar to those seen in Fc gamma RIIIA(-/)-mice. Furthermore, OVA-pulsed Fc gamma RIIIA(-/)-DCs, similar to OVA-specific Fc gamma RIIIA(-/-), had enhanced capacity to activate OVA-specific OT-II T cells, which was even further pronounced when DCs were pulsed with IgG1-complexed OVA. Our data support an inhibitory-regulatory role of Fc gamma RIIIA on vaccine/ adjuvant-induced immune responses and demonstrate that lack of Fc gamma RIIIA can promote rather than suppress both humoral and cellular immune responses.
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| 13. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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Mucosally induced immunological tolerance, regulatory T cells and the adjuvant effect by cholera toxin B subunit.
- 2010
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Ingår i: Scandinavian journal of immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 71:1, s. 1-11
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Forskningsöversikt (refereegranskat)abstract
- Induction of peripheral immunological tolerance by mucosal administration of selected antigens (Ags) ('oral tolerance') is an attractive, yet medically little developed, approach to prevent or treat selected autoimmune or allergic disorders. A highly effective way to maximize oral tolerance induction for immunotherapeutic purposes is to administer the relevant Ag together with, and preferably linked to the non-toxic B subunit protein of cholera toxin (CTB). Oral, nasal or sublingual administration of such Ag/CTB conjugates or gene fusion proteins have been found to induce tolerance with superior efficiency compared with administration of Ag alone, including the suppression of various autoimmune disorders and allergies in animal models. In a proof-of-concept clinical trial in patients with Behcet's disease, this was extended with highly promising results to prevent relapse of autoimmune uveitis. Tolerization by mucosal Ag/CTB administration results in a strong increase in Ag-specific regulatory CD4(+) T cells, apparently via two separate pathways: one using B cells as APCs and leading to a strong expansion of Foxp3(+) Treg cells which can both suppress and mediate apoptotic depletion of effector T cells, and one being B cell-independent and associated with development of Foxp3(-) regulatory T cells that express membrane latency-associated peptide and transforming growth factor (TGF-beta) and/or IL-10. The ability of CTB to dramatically increase mucosal Ag uptake and presentation by different APCs through binding to GM1 ganglioside (which makes most B cells effective APCs irrespective of their Ag specificity), together with CTB-mediated stimulation of TGF-beta and IL-10 production and inhibition of IL-6 formation may explain the dramatic potentiation of oral tolerance by mucosal Ags presented with CTB.
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| 14. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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Oral tolerance induction with antigen conjugated to cholera toxin B subunit generates both Foxp3+CD25+ and Foxp3-CD25- CD4+ regulatory T cells.
- 2006
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 177:11, s. 7634-44
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Tidskriftsartikel (refereegranskat)abstract
- Oral administration of Ag coupled to cholera toxin B subunit (CTB) efficiently induces peripheral immunological tolerance. We investigated the extent to which this oral tolerance is mediated by CD25+CD4+ regulatory T cells (T(reg)). We found that total T(reg), KJ1-26+ T(reg) and CTLA-4+ T(reg) were all increased in Peyer's patches, mesenteric lymph nodes, and, to a lesser extent, in spleen of mice after intragastric administration of OVA/CTB conjugate, which also increased TGF-beta in serum. This could be abolished by co-administering cholera toxin or by treatment with anti-TGF-beta mAb. CD25+ T(reg), but also CD25-CD4+ T cells from OVA/CTB-treated BALB/c or DO11.10 mice efficiently suppressed effector T cell proliferation and IL-2 production in vitro. Following adoptive transfer, both T cell populations also suppressed OVA-specific T cell and delayed-type hypersensitivity responses in vivo. Foxp3 was strongly expressed by CD25+ T(reg) from OVA/CTB-treated mice, and treatment also markedly expanded CD25+Foxp3+ T(reg). Furthermore, in Rag1(-/-) mice that had adoptively received highly purified Foxp3-CD25-CD4+ OT-II T cells OVA/CTB feeding efficiently induced CD25+ T(reg) cells, which expressed Foxp3 more strongly than naturally developing T(reg) and also had stronger ability to suppress effector OT-II T cell proliferation. A remaining CD25- T cell population, which also became suppressive in response to OVA/CTB treatment, did not express Foxp3. Our results demonstrate that oral tolerance induced by CTB-conjugated Ag is associated with increase in TGF-beta and in both the frequency and suppressive capacity of Foxp3+ and CTLA-4+ CD25+ T(reg) together with the generation of both Foxp3+ and Foxp3-CD25- CD4+ T(reg).
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| 15. |
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| 16. |
- Svensson, Alexandra, 1978, et al.
(författare)
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Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet.
- 2005
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 174:10, s. 6266-73
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Tidskriftsartikel (refereegranskat)abstract
- We show, for the first time, that the transcription factor T-bet, which is implicated in IFN-gamma production, is required for the induction of vaccine-induced antiviral immune protection. T-bet was found to be important in both the innate and acquired immune protection against genital HSV-2 infection. T-bet(-/-) and T-bet(+/+) mice were infected vaginally with HSV-2 and examined daily for disease and mortality. T-bet(-/-) mice had significantly higher virus titers than T-bet(+/+) mice following a primary HSV-2 infection, and succumbed significantly earlier to the infection. This result was associated with an impaired NK cell cytotoxic capacity and NK cell-mediated IFN-gamma production in the T-bet(-/-) mice. To assess the induction of acquired antiviral immune protection, mice were vaccinated with an attenuated virus before infection. Vaccinated T-bet(-/-) mice could not control viral replication following an HSV-2 challenge and had significantly higher virus titers and mortality rates than vaccinated T-bet(+/+) mice that remained healthy. The impaired acquired immune protection in T-bet(-/-) mice was associated with a significantly decreased HSV-2-specific delayed-type hypersensitivity response and a significantly reduced HSV-2-specific IFN-gamma production from CD4(+) T cells. However, T-bet deficiency did not impair either the IFN-gamma production or the cytotoxic capacity of HSV-2-specific CD8(+) T cells. We conclude that T-bet plays a crucial role in both the innate defense and the generation of vaccine-induced immunity against genital HSV-2 infection in mice.
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