| 1. |
- Hadad, Ronza, 1984-, et al.
(författare)
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Protection against genital tract Chlamydia trachomatis infection following intranasal immunization with a novel recombinant MOMP VS2/4 antigen
- 2016
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Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - Hoboken, USA : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 124, s. 1078-1086
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Tidskriftsartikel (refereegranskat)abstract
- The asymptomatic nature of most Chlamydia trachomatis infections and the lack of appropriate effects by current prevention and management call for vaccine development. We evaluated a recombinant subunit vaccine candidate based on the major outer membrane protein variable segments 2 and 4 (MOMP VS2/4). To achieve maximal immunogenicity and ease of production and purification, MOMP VS2/4 was constructed by using highly immunogenic sequences of MOMP only, thereby minimizing the presence of hydrophobic regions, and spacing the immunogenic epitopes with a flexible amino acid sequence. A purification tag was also added. The MOMP VS2/4 was given intranasally, with or without intravaginal boost, with cholera toxin (CT) adjuvant to C57BL/6 mice, which were screened for immunogenicity and protection against a live challenge infection with C. trachomatis serovar D. Bacterial shedding, cell-mediated responses, and antibody responses were monitored. Immunized mice exhibited significantly less bacterial shedding and were better protected against infertility as compared to unimmunized control mice. Immunizations stimulated both systemic and local specific antibody (IgG1, IgG2c, and IgA) responses, and primed T cells that produced interferon-c and interleukins 13 and 17 upon challenge with recall antigen. Thus, MOMP VS2/4, in combination with CT adjuvant, stimulated Th1, Th2, and Th17 effector cells, and generated protective immunity associated with less pathology. We regard MOMP VS2/4 as a promising candidate for further development into a mucosal chlamydial vaccine.
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| 2. |
- Marks, Ellen, 1982, et al.
(författare)
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CD4(+) T-cell immunity in the female genital tract is critically dependent on local mucosal immunization.
- 2011
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Ingår i: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 41:9, s. 2642-53
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Tidskriftsartikel (refereegranskat)abstract
- Immunizations via the i.n. and intravaginal (ivag) routes effectively generate strong genital tract antibody-mediated immunity. To what extent the same is true for T-cell responses is incompletely known. Therefore, we set out to investigate optimal conditions for stimulation of genital tract CD4(+) T-cell responses, using adoptive transfer of mouse DO11.10 TCR transgenic T cells specific for OVA and OVA conjugated to cholera toxin (CT) as an immunogen. We observed that progesterone was required for a T-cell response following ivag immunization, whereas estradiol prevented a response. Although i.n. immunization stimulated OVA-specific CD4(+) T-cell responses in the draining LNs, it was substantially less effective compared to ivag. More importantly, an ivag booster immunization was absolutely required to attract T cells to the genital tract mucosa itself. While clinical use of CT is precluded because of its toxicity, we developed a combined adjuvant vector based on a non-toxic derivative of CT and immune-stimulating complexes. The CTA1-DD/immune-stimulating complexes (ISCOMs) adjuvant together with major outer membrane protein was effective at stimulating genital tract CD4(+) T-cell immunity and protection against a live chlamydial infection, which holds promise for the development of mucosal vaccines against sexually transmitted infections.
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| 3. |
- Marks, Ellen, 1982, et al.
(författare)
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Differential CD28 and inducible costimulatory molecule signaling requirements for protective CD4+ T-cell-mediated immunity against genital tract Chlamydia trachomatis infection.
- 2007
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Ingår i: Infection and immunity. - 0019-9567. ; 75:9, s. 4638-47
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Tidskriftsartikel (refereegranskat)abstract
- Th1 cells and gamma interferon (IFN-gamma) production play critical roles in protective immunity against genital tract infections by Chlamydia trachomatis. Here we show that inducible costimulatory molecule (ICOS)(-/-) mice develop greatly augmented host resistance against chlamydial infection. Protection following a primary infection was characterized by strong Th1 immunity with enhanced CD4(+) T-cell-mediated IFN-gamma production in the genital tract and high expression of T-bet in the draining para-aortic lymph node. This Th1 dominance was associated with low expression of interleukin 10 (IL-10) mRNA in the uteruses of protected ICOS(-/-) mice. By contrast, CD28(-/-) mice were severely impaired in their adaptive immune response, demonstrating a lack of CD4(+) T cells and IFN-gamma in the genital tract, with a substantial delay in bacterial elimination compared to that seen in wild-type (WT) mice. Upon reinfection, WT mice exhibited a transient local infection with evidence of regulatory T-cell (Treg)/Foxp3 mRNA and a more balanced Th1 and Th2 response in the genital tract than ICOS(-/-) mice, whereas 90% of the latter mice developed sterile immunity, poor expression of local Treg/Foxp3 mRNA, and macroscopic signs of enhanced local immunopathology. Therefore, different requirements for CD28 signaling and ICOS signaling clearly apply to host protection against a genital tract infection by C. trachomatis. Whereas, CD28 signaling is critical, ICOS appears to be dispensable and can have a dampening effect on Th1 development by driving Th2 immunity and anti-inflammation through IL-10 production and promotion of the Foxp3(+) Treg populations in the genital tract. Both the CD28-deficient and the ICOS-deficient mice demonstrated poor specific antibody production, supporting the fact that antibodies are not needed for protection against genital tract chlamydial infections.
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| 4. |
- Marks, Ellen, 1982
(författare)
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Genital tract CD4+ T cells for vaccination and protection against Chlamydia trachomatis
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vaccination strategies for protection against sexually transmitted diseases (STDs) are lacking due to an incomplete understanding of genital tract T cell responses. This thesis dissects the generation of T helper subsets, including the recently discovered Th17 subset, during genital tract infection with a common sexually transmitted pathogen, Chlamydia trachomatis, and addresses vaccine requirements for the generation of genital tract CD4+ T cell immunity. Our studies demonstrate the presence of anatomically distinct T helper differentiation patterns in the genital tract. C57BL/6 mice were infected with C. trachomatis and the response in the upper genital tract (UGT) was found to be dominated by Th1 cells, whereas the lower genital tract (LGT) hosted Th2 cells in the presence of IL-10-producing DCs. Additionally, Treg and Th17 responses were demonstrated in both the UGT and LGT following infection. For the generation of T cell-mediated immunity against infection, costimulatory signals through CD28 were critical. We found that T helper differentiation and Treg responses to infection were impaired in both the UGT and LGT of CD28-/- mice. In contrast, in the absence of ICOS-signaling we observed enhanced elimination of bacteria and the development of protective immunity. Here, intense Th1 cell differentiation dominated and we found reduced regulation through both IL-10 and FoxP3+ Tregs. Paradoxically, in mice lacking both CD28 and ICOS molecules (DKO), primary infection with C. trachomatis was eliminated more rapidly than in CD28-/- mice. These mice failed to develop protective immunity against reinfection similarly to CD28-/- mice. As in ICOS-/- mice, Th1 differentiation in the LGT was enhanced in DKO mice. This indicated that ICOS costimulation modulates the immune response even in the absence of CD28-signaling, leading to augmented inflammatory immune responses in the genital tract during C. trachomatis infection. The generation of CD4+ T cell immunity is also key to vaccination against other STDs. Because of this we studied intravaginal (i.vag) immunization for priming of CD4+ T cells in the genital tract. We investigated the requirements for progesterone or estradiol for successful immunization. Both intranasal and i.vag delivery of cholera toxin conjugated to ovalbumin peptide (CT-OVA) induced T cell responses in the draining lymph node, however, i.vag immunizations were absolutely required in order to attract T cells to the genital tract mucosa. In conclusion, the results presented in this thesis provide evidence of anatomically divided T cell immune responses to C. trachomatis in the genital tract. Understanding of T cell responses in the genital tract are has important implications for the generation of protective immunity and immunopathology.
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| 5. |
- Marks, Ellen, 1982, et al.
(författare)
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Genital Tract T cells
- 2004
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Ingår i: Mucosal Immunology Update. - 1068-7629. ; 12:3, s. 8-11
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Marks, Ellen, 1982, et al.
(författare)
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Immunity against Chlamydia trachomatis
- 2008
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Ingår i: Immunity against mucosal pathogens Ed Michael Vajdy. - 9781402084119 ; , s. 433-457
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Marks, Ellen, 1982, et al.
(författare)
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The female lower genital tract is a privileged compartment with IL-10 producing dendritic cells and poor Th1 immunity following Chlamydia trachomatis infection.
- 2010
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- While a primary genital tract infection with C. trachomatis stimulates partial-protection against re-infection, it may also result in severe inflammation and tissue destruction. Here we have dissected whether functional compartments exist in the genital tract that restrict Th1-mediated protective immunity. Apart from the Th1-subset, little is known about the role of other CD4(+) T cell subsets in response to a genital tract chlamydial infection. Therefore, we investigated CD4(+) T cell subset differentiation in the genital tract using RT-PCR for expression of critical transcription factors and cytokines in the upper (UGT) and lower genital tract (LGT) of female C57BL/6 mice in response to C. trachomatis serovar D infection. We found that the Th1 subset dominated the UGT, as IFN-γ and T-bet mRNA expression were high, while GATA-3 was low following genital infection with C. trachomatis serovar D. By contrast, IL-10 and GATA-3 mRNA dominated the LGT, suggesting the presence of Th2 cells. These functional compartments also attracted regulatory T cells (Tregs) differently as increased FoxP3 mRNA expression was seen primarily in the UGT. Although IL-17A mRNA was somewhat up-regulated in the LGT, no significant change in RORγ-t mRNA expression was observed, suggesting no involvement of Th17 cells. The dichotomy between the LGT and UGT was maintained during infection by IL-10 because in IL-10-deficient mice the distinction between the two compartments was completely lost and a dramatic shift to the predominance of Th1 cells in the LGT occurred. Unexpectedly, the major source of IL-10 was CD11c(+) CD11b(+) DC, probably creating an anti-inflammatory privileged site in the LGT.
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| 8. |
- Pantazi, E., et al.
(författare)
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Cutting Edge: Retinoic Acid Signaling in B Cells Is Essential for Oral Immunization and Microflora Composition
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 195:4, s. 1368-1371
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Tidskriftsartikel (refereegranskat)abstract
- Retinoic acid (RA) is a critical regulator of the intestinal adaptive immune response. However, the intrinsic impact of RA on B cell differentiation in the regulation of gut humoral immunity in vivo has never been directly shown. To address this issue, we have been able to generate a mouse model where B cells specifically express a dominant-negative receptor a for RA. In this study, we show that the silencing of RA signaling in B cells reduces the numbers of IgA(+) Ab-secreting cells both in vitro and in vivo, suggesting that RA has a direct effect on IgA plasma cell differentiation. Moreover, the lack of RA signaling in B cells abrogates Ag-specific IgA responses after oral immunization and affects the microbiota composition. In conclusion, these results suggest that RA signaling in B cells through the RA receptor a is important to generate an effective gut humoral response and to maintain a normal microbiota composition.
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