| 1. |
- Bernasconi, Valentina, 1989, et al.
(author)
-
A vaccine combination of lipid nanoparticles and a cholera toxin adjuvant derivative greatly improves lung protection against influenza virus infection
- 2021
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In: Mucosal Immunology. - : Elsevier BV. - 1933-0219 .- 1935-3456. ; 14:2, s. 523-536
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Journal article (peer-reviewed)abstract
- This is a proof-of-principle study demonstrating that the combination of a cholera toxin derived adjuvant, CTA1-DD, and lipid nanoparticles (LNP) can significantly improve the immunogenicity and protective capacity of an intranasal vaccine. We explored the self-adjuvanted universal influenza vaccine candidate, CTA1-3M2e-DD (FPM2e), linked to LNPs. We found that the combined vector greatly enhanced survival against a highly virulent PR8 strain of influenza virus as compared to when mice were immunized with FPM2e alone. The combined vaccine vector enhanced early endosomal processing and peptide presentation in dendritic cells and upregulated co-stimulation. The augmenting effect was CTA1-enzyme dependent. Whereas systemic anti-M2e antibody and CD4(+)T-cell responses were comparable to those of the soluble protein, the local respiratory tract IgA and the specific Th1 and Th17 responses were strongly enhanced. Surprisingly, the lung tissue did not exhibit gross pathology upon recovery from infection and M2e-specific lung resident CD4(+)T cells were threefold higher than in FPM2e-immunized mice. This study conveys optimism as to the protective ability of a combination vaccine based on LNPs and various forms of the CTA1-DD adjuvant platform, in general, and, more specifically, an important way forward to develop a universal vaccine against influenza.
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| 2. |
- Grdic Eliasson, Dubravka, et al.
(author)
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A novel non-toxic combined CTA1-DD and ISCOMS adjuvant vector for effective mucosal immunization against influenza virus.
- 2011
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In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 29:23, s. 3951-61
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Journal article (peer-reviewed)abstract
- Here we demonstrate that by using non-toxic fractions of saponin combined with CTA1-DD we can achieve a safe and above all highly efficacious mucosal adjuvant vector. We optimized the construction, tested the requirements for function and evaluated proof-of-concept in an influenza A virus challenge model. We demonstrated that the CTA1-3M2e-DD/ISCOMS vector provided 100% protection against mortality and greatly reduced morbidity in the mouse model. The immunogenicity of the vector was superior to other vaccine formulations using the ISCOM or CTA1-DD adjuvants alone. The versatility of the vector was best exemplified by the many options to insert, incorporate or admix vaccine antigens with the vector. Furthermore, the CTA1-3M2e-DD/ISCOMS could be kept 1 year at 4°C or as a freeze-dried powder without affecting immunogenicity or adjuvanticity of the vector. Strong serum IgG and mucosal IgA responses were elicited and CD4 T cell responses were greatly enhanced after intranasal administration of the combined vector. Together these findings hold promise for the combined vector as a mucosal vaccine against influenza virus infections including pandemic influenza. The CTA1-DD/ISCOMS technology represents a breakthrough in mucosal vaccine vector design which successfully combines immunomodulation and targeting in a safe and stable particulate formation.
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| 3. |
- Helgeby, Anja, 1967, et al.
(author)
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The combined CTA1-DD/ISCOM adjuvant vector promotes priming of mucosal and systemic immunity to incorporated antigens by specific targeting of B cells.
- 2006
-
In: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 176:6, s. 3697-706
-
Research review (peer-reviewed)abstract
- The cholera toxin A1 (CTA1)-DD/QuilA-containing, immune-stimulating complex (ISCOM) vector is a rationally designed mucosal adjuvant that greatly potentiates humoral and cellular immune responses. It was developed to incorporate the distinctive properties of either adjuvant alone in a combination that exerted additive enhancing effects on mucosal immune responses. In this study we demonstrate that CTA1-DD and an unrelated Ag can be incorporated together into the ISCOM, resulting in greatly augmented immunogenicity of the Ag. To demonstrate its relevance for protection against infectious diseases, we tested the vector incorporating PR8 Ag from the influenza virus. After intranasal immunization we found that the immunogenicity of the PR8 proteins were significantly augmented by a mechanism that was enzyme dependent, because the presence of the enzymatically inactive CTA1R7K-DD mutant largely failed to enhance the response over that seen with ISCOMs alone. The combined vector was a highly effective enhancer of a broad range of immune responses, including specific serum Abs and balanced Th1 and Th2 CD4(+) T cell priming as well as a strong mucosal IgA response. Unlike unmodified ISCOMs, Ag incorporated into the combined vector could be presented by B cells in vitro and in vivo as well as by dendritic cells; it also accumulated in B cell follicles of draining lymph nodes when given s.c. and stimulated much enhanced germinal center reactions. Strikingly, the enhanced adjuvant activity of the combined vector was absent in B cell-deficient mice, supporting the idea that B cells are important for the adjuvant effects of the combined CTA1-DD/ISCOM vector.
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| 4. |
- Agrawal, K., et al.
(author)
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Allergic sensitization impairs lung resident memory CD8 T-cell response and virus clearance
- 2022
-
In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 150:6
-
Journal article (peer-reviewed)abstract
- Background: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections. Objective: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance. Methods: Mice were sensitized with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Antiviral memory T-cell response and protection to viral infection was assessed before and after secondary influenza infection, respectively. Gene set variation analysis was performed on data sets from the U-BIOPRED asthma cohort using an IFN-γ–induced epithelial cell signature and a tissue resident memory T-cell signature. Results: Viral loads were higher in lungs of sensitized compared with nonsensitized mice after secondary infection, indicating reduced virus clearance. X47 priming induced fewer antiviral lung resident memory CD8 T cells and resulted in lower pulmonary IFN-γ levels in the lungs of sensitized as compared with nonsensitized mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFN-γ–induced genes in nasal brushings and bronchial biopsies were also enriched in resident memory T-cell–associated genes, had more epithelial CD8 T cells, and reported significantly fewer exacerbations. Conclusions: The allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance. Defective antiviral memory response might contribute to increased susceptibility of patients with asthma to viral exacerbations.
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| 5. |
- Akhiani, Aliasghar, 1957, et al.
(author)
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IgA antibodies impair resistance against Helicobacter pylori infection: studies on immune evasion in IL-10-deficient mice.
- 2005
-
In: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 174:12, s. 8144-53
-
Journal article (peer-reviewed)abstract
- We recently reported that Helicobacter pylori-specific Abs impair the development of gastritis and down-regulate resistance against H. pylori infection. In this study, we asked whether IgA Abs specifically can have an impact on H. pylori colonization and gastric inflammation. To obtain a sensitive model for the study of inflammation we crossed IgA- and IL-10-deficient mice. We found that IL-10(-/-)/IgA(-/-) mice were significantly less colonized than IL-10(-/-)/IgA(+/+) mice, which in turn were less colonized than wild-type (WT) mice. The IL-10(-/-)/IgA(-/-) mice exhibited a 1.2-log reduction in bacterial counts compared with that in IL-10(-/-)/IgA(+/+) mice, suggesting that IgA Abs rather promoted than prevented infection. The reduced colonization in IL-10(-/-)/IgA(-/-) mice was associated with the most severe gastritis observed, albeit all IL-10(-/-) mice demonstrated more severe gastric inflammation than wild-type mice. The gastritis score and the infiltration of CD4(+) T cells into the gastric mucosa were significantly higher in IL-10(-/-)/IgA(-/-) mice than in IL-10(-/-)/IgA(+/+) mice, arguing that IgA Abs counteracted inflammation. Moreover, following oral immunization, IL-10(-/-)/IgA(-/-) mice were significantly better protected against colonization than IL-10(-/-)/IgA(+/+) mice. However, the stronger protection was associated with more severe postimmunization gastritis and gastric infiltration of CD4(+) T cells. There was also a clear increase in complement receptor-expressing cells in IL-10(-/-)/IgA(-/-) mice, though C3b-fragment deposition in the gastric mucosa was comparable between the two. Finally, specific T cell responses to recall Ag demonstrated higher levels of IFN-gamma production in IL-10(-/-)/IgA(-/-) as compared with IL-10(-/-)/IgA(+/+) mice. Thus, it appears that IgA and IL-10 help H. pylori bacteria evade host resistance against infection.
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| 6. |
- Akhiani, Aliasghar, 1957, et al.
(author)
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The nontoxic CTA1-DD adjuvant enhances protective immunity against Helicobacter pylori infection following mucosal immunization.
- 2006
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In: Scandinavian journal of immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 63:2, s. 97-105
-
Journal article (peer-reviewed)abstract
- Safe and efficacious adjuvants are much needed to facilitate the development of mucosal vaccines. Here, we have asked whether our nontoxic vaccine adjuvant, CTA1-DD, can enhance protective immunity against Helicobacter pylori infection. Intranasal immunizations with H. pylori lysate together with CTA1-DD-adjuvant induced significant protection in C57Bl/6 mice, almost as strong as similar immunizations using cholera toxin (CT)-adjuvant. Protection remained strong even at 8 weeks postchallenge and the bacterial colonization was reduced by 20-fold compared to lysate-immunized controls. Although CTA1-DD was designed to bind to B cells, microMT mice developed significant, but lower, level of protection following immunization. Intranasal immunizations with CT adjuvant in C57Bl/6 mice resulted in the development of severe postimmunization gastritis at 2 and 8 weeks postchallenge, whereas the degree of gastritis was substantially lower in the CTA1-DD-immunized mice. Protection induced by both CTA1-DD- and CT adjuvant was associated with a strong local infiltration of CD4(+) T cells in the gastric mucosa, and recall responses to specific Ag elicited substantial IFN-gamma production, indicating Th1-dominance. These findings clearly demonstrate that CTA1-DD adjuvant is a promising candidate to be further exploited in the development of a mucosal vaccine against H. pylori infection.
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| 7. |
- Akhiani, Aliasghar, 1957, et al.
(author)
-
Vaccine-induced immunity against Helicobacter pylori infection is impaired in IL-18-deficient mice.
- 2004
-
In: Journal of immunology. - 0022-1767. ; 173:5, s. 3348-56
-
Research review (peer-reviewed)abstract
- Protective immunity against Helicobacter pylori infection in mice has been associated with a strong Th1 response, involving IL-12 as well as IFN-gamma, but recent studies have also demonstrated prominent eosinophilic infiltration, possibly linked to local Th2 activity in the gastric mucosa. In this study we investigated the role of IL-18, because this cytokine has been found to be a coregulator of Th1 development as well as involved in Th2-type responses with local eotaxin production that could influence gastric eosinophilia and resistance to infection. We found that IL-18(-/-) mice failed to develop protection after oral immunization with H. pylori lysate and cholera toxin adjuvant, indicating an important role of IL-18 in protection. Well-protected C57BL/6 wild-type (WT) mice demonstrated substantial influx of CD4(+) T cells and eosinophilic cells in the gastric mucosa, whereas IL-18(-/-) mice had less gastritis, few CD4(+) T cells, and significantly reduced numbers of eosinophilic cells. T cells in well-protected WT mice produced increased levels of IFN-gamma and IL-18 to recall Ag. By contrast, unprotected IL-18(-/-) mice exhibited significantly reduced gastric IFN-gamma and specific IgG2a Ab levels. Despite differences in gastric eosinophilic cell infiltration, protected WT and unprotected IL-18(-/-) mice had comparable levels of local eotaxin, suggesting that IL-18 influences protection via Th1 development and IFN-gamma production rather than through promoting local production of eotaxin and eosinophilic cell infiltration.
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| 8. |
- Arabpour, Mohammad, et al.
(author)
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ADP-ribosylating adjuvant reveals plasticity in cDC1 cells that drive mucosal Th17 cell development and protection against influenza virus infection
- 2022
-
In: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 15:4, s. 745-761
-
Journal article (peer-reviewed)abstract
- Migratory dendritic cells expressing CD103 are the targets for mucosal vaccines. These belong to either of two lineage-restricted subsets, cDC1 or cDC2 cells, which have been linked to priming of functionally distinct CD4 T cells. However, recent studies have identified plasticity in cDC2 cells with overlapping functions with cDC1 cells, while the converse has not been reported. We genetically engineered a vaccine adjuvant platform that targeted the cholera toxin A1 (CTA1) ADP-ribosylating enzyme to CD103(+) cDC1 and cDC2 cells using a single-chain antibody (scFv) to CD103. Unexpectedly, intranasal immunization with the CTA1-svFcCD103 adjuvant modified cDC1 cells to effectively prime Th17 cells, a function previously limited to cDC2 cells. In fact, cDC2 cells were dispensible, while cDC1 cells, lacking in Batf3-/- mice, were critical. Following intranasal immunizations isolated cDC1 cells from mLN exclusively promoted Rorgt(+) T cells and IL-17, IL-21, and IL-22 production. Strong CD8 T cell responses through antigen cross presentation by cDC1 cells were also observed. Single-cell RNAseq analysis revealed upregulation of Th17-promoting gene signatures in sorted cDC1 cells. Gene expression in isolated cDC2 cells was largely unaffected. Our finding represents a major shift of paradigm as we have documented functional plasticity in cDC1 cells.
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| 9. |
- Bernasconi, Valentina, 1989, et al.
(author)
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Porous Nanoparticles With Self-Adjuvanting M2e-Fusion Protein and Recombinant Hemagglutinin Provide Strong and Broadly Protective Immunity Against Influenza Virus Infections
- 2018
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
-
Journal article (peer-reviewed)abstract
- Due to the high risk of an outbreak of pandemic influenza, the development of a broadly protective universal influenza vaccine is highly warranted. The design of such a vaccine has attracted attention and much focus has been given to nanoparticle-based influenza vaccines which can be administered intranasally. This is particularly interesting since, contrary to injectable vaccines, mucosal vaccines elicit local IgA and lung resident T cell immunity, which have been found to correlate with stronger protection in experimental models of influenza virus infections. Also, studies in human volunteers have indicated that pre-existing CD4(+) T cells correlate well to increased resistance against infection. We have previously developed a fusion protein with 3 copies of the ectodomain of matrix protein 2 (M2e), which is one of the most explored conserved influenza A virus antigens for a broadly protective vaccine known today. To improve the protective ability of the self-adjuvanting fusion protein, CTA1-3M2e-DD, we incorporated it into porous maltodextrin nanoparticles (NPLs). This proof-of-principle study demonstrates that the combined vaccine vector given intranasally enhanced immune protection against a live challenge infection and reduced the risk of virus transmission between immunized and unimmunized individuals. Most importantly, immune responses to NPLs that also contained recombinant hemagglutinin (HA) were strongly enhanced in a CTA1-enzyme dependentmanner and we achieved broadly protective immunity against a lethal infection with heterosubtypic influenza virus. Immune protection wasmediated by enhanced levels of lung resident CD4(+) T cells as well as anti-HA and -M2e serum IgG and local IgA antibodies.
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| 10. |
- Besavilla, Danica F, et al.
(author)
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Pre-existing CD4 T cell help boosts antibody responses but has limited impact on germinal center, antigen-specific B cell frequencies after influenza infection.
- 2023
-
In: Frontiers in immunology. - 1664-3224. ; 14
-
Journal article (peer-reviewed)abstract
- The influenza virus is a persistent burden on global health, with seasonal vaccines providing incomplete protection. CD4+ T cells help shape B cell and antibody responses; however, the selectivity of help and the effect on various antigen-specific B cell populations have not been fully elucidated. Here, we studied the specificity, selectivity, and influence of nucleoprotein (NP) CD4+ T cells on the magnitude and quality of hemagglutinin (HA) and NP-specific B cells and antibody responses. We identified immunodominant peptides and showed that peptide immunization was sufficient to induce CD4+ cells with Th1 and Tfh phenotypes. Surprisingly, while preexisting CD4+ T cells enhanced the influx of total germinal center (GC) B cells in the mediastinal lymph node after infection, this was not reflected by an increase in the frequency of antigen-specific cells within the GC. Furthermore, we demonstrated that NP-specific help was able to accelerate the kinetics and magnitude of the Ab response for NP but not for HA. Overall, our results showed that pre-existing CD4+ T cells provide strong cognate help during immunization or infection to enhance Ab production but not antigen-specific GC or memory B cells.
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| 11. |
- Consonni, A., et al.
(author)
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A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using Targeted Fusion Protein, mCTA1-T146
- 2017
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
-
Journal article (peer-reviewed)abstract
- Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1-T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGF beta, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1-T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1-T146 is a promising candidate for clinical evaluation in myasthenia gravis patients.
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| 12. |
- Eriksson, Anna M, et al.
(author)
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The cholera toxin-derived CTA1-DD vaccine adjuvant administered intranasally does not cause inflammation or accumulate in the nervous tissues.
- 2004
-
In: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 173:5, s. 3310-9
-
Research review (peer-reviewed)abstract
- Although highly effective, the use of GM1-receptor binding holotoxins as nasal mucosal adjuvants has recently been cautioned due to the risk for their accumulation in the brain and other nervous tissues. Therefore we have explored the efficacy of the CTA1-DD adjuvant for its ability to enhance nasal immune responses in mice. We found that despite the lack of a mucosal binding element, the B cell-targeted CTA1-DD molecule was an equally strong adjuvant as cholera toxin (CT). The potency of CTA1-DD was not a result of endotoxin contamination because more than a 50-fold higher dose of LPS was needed to achieve a similar enhancement. Moreover, the adjuvant effect was TLR4-independent and absent in mutant CTA1-E112K-DD, lacking enzymatic activity. The CTA1-DD adjuvant augmented germinal center formations and T cell priming in the draining lymph nodes, and contrary to CT, promoted a balanced Th1/Th2 response with little effect on IgE Ab production. CTA1-DD did not induce inflammatory changes in the nasal mucosa, and most importantly did not bind to or accumulate in the nervous tissues of the olfactory bulb, whereas CT bound avidly to the nervous tissues. We believe that the nontoxic CTA1-DD adjuvant is an attractive solution to the current dilemma between efficacy and toxicity encountered in CT-holotoxin adjuvant or Escherichia coli heat-labile toxin-holotoxin adjuvant strategies and provides a safe and promising candidate to be included in future vaccines for intranasal administration.
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| 13. |
- Grdic, Dubravka, 1968, et al.
(author)
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Splenic marginal zone dendritic cells mediate the cholera toxin adjuvant effect: dependence on the ADP-ribosyltransferase activity of the holotoxin.
- 2005
-
In: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 175:8, s. 5192-202
-
Research review (peer-reviewed)abstract
- The in vivo mechanisms of action of most vaccine adjuvants are poorly understood. In this study, we present data in mice that reveal a series of critical interactions between the cholera toxin (CT) adjuvant and the dendritic cells (DC) of the splenic marginal zone (MZ) that lead to effective priming of an immune response. For the first time, we have followed adjuvant targeting of MZ DC in vivo. We used CT-conjugated OVA and found that the Ag selectively accumulated in MZ DC following i.v. injections. The uptake of Ag into DC was GM1 ganglioside receptor dependent and mediated by the B subunit of CT (CTB). The targeted MZ DC were quite unique in their phenotype: CD11c(+), CD8alpha(-), CD11b(-), B220(-), and expressing intermediate or low levels of MHC class II and DEC205. Whereas CTB only delivered the Ag to MZ DC, the ADP-ribosyltransferase activity of CT was required for the maturation and migration of DC to the T cell zone, where these cells distinctly up-regulated CD86, but not CD80. This interaction appeared to instruct Ag-specific CD4(+) T cells to move into the B cell follicle and strongly support germinal center formations. These events may explain why CT-conjugated Ag is substantially more immunogenic than Ag admixed with soluble CT and why CTB-conjugated Ag can tolerize immune responses when given orally or at other mucosal sites.
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| 14. |
- Grdic Eliasson, Dubravka, et al.
(author)
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CTA1-M2e-DD: a novel mucosal adjuvant targeted influenza vaccine.
- 2008
-
In: Vaccine. - : Elsevier BV. - 0264-410X. ; 26:9, s. 1243-52
-
Journal article (peer-reviewed)abstract
- At present few vaccine candidates exists against potentially pandemic influenza virus infections. We provide compelling evidence that a targeted fusion protein based on the CTA1-DD adjuvant and containing tandem repeats of the matrix protein 2 (M2e) ectodomain epitope, CTA1-3M2e-DD, confers strong protective immunity against a potentially lethal challenge infection with influenza virus in mice. The formulation was highly effective for mucosal immunizations and promoted high M2e-specific serum IgG and mucosal IgA antibody titers and an hitherto unknown anti-M2e CD4 T cell immunity. This novel CTA1-3M2e-DD fusion protein combines adjuvant and a conserved influenza A antigen in a promising candidate for a universal anti-influenza vaccine.
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| 15. |
- Grdic Eliasson, Dubravka, et al.
(author)
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M2e-tetramer-specific memory CD4 T cells are broadly protective against influenza infection.
- 2018
-
In: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 11:1, s. 273-289
-
Journal article (peer-reviewed)abstract
- Matrix protein 2 ectodomain (M2e) is considered an attractive component of a broadly protective, universal influenza A vaccine. Here we challenge the canonical view that antibodies against M2e are the prime effectors of protection. Intranasal immunizations of Balb/c mice with CTA1-3M2e-DD-generated M2e-specific memory CD4 T cells that were I-Ad restricted and critically protected against infection, even in the complete absence of antibodies, as observed in JhD mice. Whereas some M2e-tetramer-specific memory CD4 T cells resided in spleen and lymph nodes, the majority were lung-resident Th17 cells, that rapidly expanded upon a viral challenge infection. Indeed, immunized IL-17A-/- mice were significantly less well protected compared with wild-type mice despite exhibiting comparable antibody levels. Similarly, poor protection was also observed in congenic Balb/B (H-2b) mice, which failed to develop M2e-specific CD4 T cells, but exhibited comparable antibody levels. Lung-resident CD69+ CD103low M2e-specific memory CD4 T cells were αβ TCR+ and 50% were Th17 cells that were associated with an early influx of neutrophils after virus challenge. Adoptively transferred M2e memory CD4 T cells were strong helper T cells, which accelerated M2e- but more importantly also hemagglutinin-specific IgG production. Thus, for the first time we demonstrate that M2e-specific memory CD4 T cells are broadly protective.Mucosal Immunology advance online publication 15 March 2017. doi:10.1038/mi.2017.14.
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| 16. |
- Gribonika, Inta, et al.
(author)
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Class-switch recombination to IgA in the Peyer's patches requires natural thymus-derived Tregs and appears to be antigen independent.
- 2019
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In: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 12:6, s. 1268-1279
-
Journal article (peer-reviewed)abstract
- Our understanding of how class-switch recombination (CSR) to IgA occurs in the gut is still incomplete. Earlier studies have indicated that Tregs are important for IgA CSR and these cells were thought to transform into follicular helper T cells (Tfh), responsible for germinal center formation in the Peyer's patches (PP). Following adoptive transfer of T-cell receptor-transgenic (TCR-Tg) CD4 T cells into nude mice, we unexpectedly found that oral immunization did not require an adjuvant to induce strong gut IgA and systemic IgG responses, suggesting an altered regulatory environment in the PP. After sorting of splenic TCR-Tg CD4 T cells into CD25+ or CD25- cells we observed that none of these fractions supported a gut IgA response, while IgG responses were unperturbed in mice receiving the CD25- cell fraction. Hence, while Tfh functions resided in the CD25- fraction the IgA CSR function in the PP was dependent on CD25+ Foxp3+ Tregs, which were found to be Helios+ neuropilin-1+ thymus-derived Tregs. This is the first study to demonstrate that Tfh and IgA CSR functions are indeed, unique, and separate functions in the PP with the former being TCR-dependent while the latter appeared to be antigen independent.
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| 17. |
- Gribonika, Inta, et al.
(author)
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Peyer's patch TH17 cells are dispensable for gut IgA responses to oral immunization.
- 2022
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In: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 7:73
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Journal article (peer-reviewed)abstract
- T helper 17 (TH17) cells located at the Peyer's patch (PP) inductive site and at the lamina propria effector site of the intestinal immune system are responsive to both pathogenic and commensal bacteria. Their plasticity to convert into follicular helper T (TFH) cells has been proposed to be central to gut immunoglobulin A (IgA) responses. Here, we used an IL-17A fate reporter mouse and an MHC-II tetramer to analyze antigen-specific CD4+ T cell subsets and isolate them for single-cell RNA sequencing after oral immunization with cholera toxin and ovalbumin. We found a TFH-dominated response with only rare antigen-specific TH17 cells (<8%) in the PP. A clonotypic analysis provided little support that clonotypes were shared between TFH and TH17 cells, arguing against TH17 plasticity as a major contributor to TFH differentiation. Two mouse models of TH17 deficiency confirmed that gut IgA responses to oral immunization do not require TH17 cells, with CD4CreRorcfl/fl mice exhibiting normal germinal centers in PP and unperturbed total IgA production in the intestine.
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| 18. |
- Hadad, Ronza, 1984-, et al.
(author)
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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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In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - Hoboken, USA : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 124, s. 1078-1086
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Journal article (peer-reviewed)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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| 19. |
- Hansson, Charlotta, et al.
(author)
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Feeding transgenic plants that express a tolerogenic fusion protein effectively protects against arthritis
- 2016
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In: Plant Biotechnology Journal. - : Wiley-Blackwell. - 1467-7644 .- 1467-7652. ; 14:4, s. 1106-1115
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Journal article (peer-reviewed)abstract
- Although much explored, oral tolerance for treatment of autoimmune diseases still awaits the establishment of novel and effective vectors. We investigated if the tolerogenic CTA1(R7K)-COL-DD fusion protein can be expressed in edible plants and in this way induce oral tolerance and protect against arthritis. The fusion protein was recombinantly expressed in Arabidopsis thaliana plants, which were fed to H-2q restricted DBA/1 mice to assess the preventive effect on collagen-induced arthritis (CIA). The treatment resulted in fewer mice exhibiting disease and arthritis scores were significantly reduced. Immune suppression was evident in treated mice and serum biomarkers for inflammation as well as anti-collagen IgG responses were reduced. In spleen draining and lymph nodes, CD4+ T cell responses were reduced. Concomitant with a reduced effector T cell activity with lower IFNg, IL-13 and IL-17A production we observed an increase in IL-10 production to recall antigen stimulation in vitro, suggesting reduced Th1, Th2 and Th17 activity subsequent to upregulated IL-10 and regulatory T cell (Treg) functions. The present study shows that edible plants expressing a tolerogen were effective at stimulating CD4 T cell tolerance and in protecting against CIA disease. Our study conveys optimism as to the potential of using edible plants for oral treatment of rheumatoid arthritis.
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| 20. |
- Hansson, Charlotta, et al.
(author)
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Tr1 cell-mediated protection against autoimmune disease by intranasal administration of a fusion protein targeting cDC1 cells.
- 2023
-
In: Mucosal immunology. - 1935-3456. ; 16:4, s. 486-498
-
Journal article (peer-reviewed)abstract
- Curative therapies against autoimmune diseases are lacking. Indeed, most of the currently available treatments are only targeting symptoms. We have developed a novel strategy for a therapeutic vaccine against autoimmune diseases based on intranasal administration of a fusion protein tolerogen, which consists of a mutant, enzymatically inactive, cholera toxin A1 (CTA1)-subunit genetically fused to disease-relevant high-affinity peptides and a dimer of D-fragments from protein A (DD). The CTA1 R7K mutant - myelin oligodendrocyte glycoprotein (MOG), or proteolipid protein (PLP) - DD (CTA1R7K-MOG/PLP-DD) fusion proteins effectively reduced clinical symptoms in the experimental autoimmune encephalitis model of multiple sclerosis. The treatment induced Tr1 cells, in the draining lymph node, which produced interleukin (IL)-10 and suppressed effector clusters of differentiation 4+ T-cell responses. This effect was dependent on IL-27 signaling because treatment was ineffective in bone marrow chimeras lacking IL-27Ra within their hematopoietic compartment. Single-cell RNA sequencing of dendritic cells in draining lymph nodes demonstrated distinct gene transcriptional changes of classic dendritic cells 1, including enhanced lipid metabolic pathways, induced by the tolerogenic fusion protein. Thus, our results with the tolerogenic fusion protein demonstrate the possibility to vaccinate and protect against disease progression by reinstating tolerance in multiple sclerosis and other autoimmune diseases.
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| 21. |
- Hasselberg, Annemarie, 1973, et al.
(author)
-
ADP-ribosylation control the outcome of tolerance or enhanced priming following mucosal immunization.
- 2010
-
In: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 184:6, s. 2776-2784
-
Journal article (peer-reviewed)abstract
- Accumulating evidence suggests that the dichotomy between tolerance and active IgA immunity in mucosal immune responses is regulated at the APC level. Therefore, immunomodulation of the APC could be an effective mechanism to control the two response patterns. In this study, we demonstrate that ADP-ribosylation controls the outcome of tolerance or active effector T cell immunity to an internal peptide p323–339 from OVA inserted into the cholera toxin (CT)-derived CTA1-OVA-DD adjuvant. We found that a single point mutation, CTA1R7K-OVA-DD, resulting in lack of enzymatic activity, promoted peptide-specific tolerance in TCR transgenic CD4+ T cells following a single intranasal (i.n.) treatment. The CTA1R7K-OVA-DD–induced tolerance was strong, long-lasting, and impaired the ability of adoptively transferred naive peptide-specific CD4+ T cells to respond to Ag-challenge, irrespective if this was given i.p or i.n. The tolerance correlated with induction of regulatory T cells of the regulatory T type 1 characterized by CD25−Foxp3−CD4+ T cells producing IL-10. In contrast, in IL-10–deficient mice, no peptide-specific tolerance was observed, and these mice exhibited unimpaired CD4+ T cell responsiveness to recall Ag irrespective of if they were untreated (PBS) or treated i.n. with CTA1R7K-OVA-DD. Thus, for the first time, we can provide unequivocal proof that ADP-ribosylation can control the outcome of mucosal Ag exposure from tolerance to an enhanced effector CD4+ T cell response. The exploitation of this system for clinical treatment of autoimmune diseases is discussed.
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| 22. |
- Hasselberg, Annemarie, 1973, et al.
(author)
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Role of CTA1R7K-COL-DD as a novel therapeutic mucosal tolerance-inducing vector for treatment of collagen-induced arthritis.
- 2009
-
In: Arthritis and rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:6, s. 1672-82
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To determine whether a cholera toxin-derived, novel immunomodulating fusion protein, CTA1R7K-COL-DD, carrying the class II major histocompatibility complex H-2q-restricted type II collagen peptide aa 259-274, can induce therapeutic tolerance and prevent collagen-induced arthritis (CIA) when administered intranasally in DBA/1 mice, and to assess whether ADP-ribosylation at the mucosal membranes exerts a regulatory function such that the outcome of tolerance or immune enhancement can be controlled. METHODS: DBA/1 mice with CIA were treated intranasally with CTA1R7K-COL-DD. The therapeutic effect was monitored for 46 days after the onset of disease. Clinical scoring of disease, histologic examination of inflammation, and bone erosion were assessed, and cytokine levels were determined in the serum or supernatants from splenocytes stimulated with recall antigen. RESULTS: The protective effect of CTA1R7K-COL-DD resulted in roughly 60% of the mice having no clinical signs or histologic evidence of disease after treatment, and those with CIA had significantly milder disease with less bone erosion. The protective status was associated with lower serum titers of IgG1, IgG2a, IgG2b, and IgG3 anticollagen and a substantial decrease in the production of interleukin-6 (IL-6), IL-17, and interferon-gamma, while levels of IL-10 were markedly up-regulated both in the serum and at the T cell level. CONCLUSION: The enzymatically inactive mutant fusion protein CTA1R7K-COL-DD provided substantial therapeutic protection against CIA following intranasal administration. The mechanism behind the effect appears to be mediated by peptide-specific regulatory T cells induced by mucosal exposure to the peptide containing CTA1R7K-COL-DD vector. In addition, ADP-ribosylation at the mucosal membranes acts as a key regulator controlling mucosal tolerance or immunity.
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| 23. |
- Kjerrulf, Martin, et al.
(author)
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Interferon-gamma receptor-deficient mice exhibit impaired gut mucosal immune responses but intact oral tolerance.
- 1997
-
In: Immunology. - 0019-2805. ; 92:1, s. 60-8
-
Journal article (peer-reviewed)abstract
- Interferon-gamma (IFN-gamma) receptor knock-out (IFN-gamma R -/-) mice were used to analyse the role of IFN-gamma in mucosal immune responses following oral immunization. We found that the IFN-gamma R -/- mice demonstrated 50% reduced spot-forming cell (SFC) responses in the gut lamina propria and spleen after oral immunization with keyhold limpet haemocyanin (KLH) plus cholera toxin (CT) adjuvant. The IFN-gamma R -/- mice exhibited 10-fold reduced total serum KLH-specific antibody levels compared with wild-type mice after oral immunization, while after intravenous immunization, no such difference was seen, suggesting a selective impairment of mucosal immune responses. Moreover, oral immunizations resulted in impaired interleukin-4 (IL-4), IL-10 and IFN-gamma production by spleen T cells from IFN-gamma R -/- mice, indicating that no reciprocal up-regulation of Th2-activities had occurred despite the lack of IFN-gamma R function. No reduction in Th1 or Th2 cytokines was observed following systemic immunizations. Despite potentially strong modulating effects of IFN-gamma on epithelial cell IgA transcytosis and electrolyte barrier functions, CT-immunized IFN-gamma R -/- mice demonstrated unaltered protection against CT in ligated intestinal loops together with normal anti-CT IgA and total IgA levels in gut lavage. Oral feeding with KLH followed by parenteral immunization resulted in strongly suppressed SFC numbers and reduced cell-mediated immunity in both wild-type and IFN-gamma R -/- mice. CT-adjuvant abrogated induction of oral tolerance in both IFN-gamma R -/- and wild-type mice. Collectively, our data argue that the two major response patterns induced by oral administration of protein antigen, i.e. active IgA immunity and oral tolerance, are differently regulated. Thus, IFN-gamma R -/- mice have impaired mucosal immune responses while induction of oral tolerance appears to be unaffected by the lack of IFN-gamma functions.
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| 24. |
- Kylén, Maya, et al.
(author)
-
Patient Participation and the Environment : A Scoping Review of Instruments
- 2022
-
In: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 19:4
-
Journal article (peer-reviewed)abstract
- Patient participation and the environment are critical factors in achieving qualitative healthcare. We conducted a systematic scoping review using Arksey and O’Malley’s framework to identify instruments intended to measure patient participation. We assessed those instruments’ characteristics, which areas of the healthcare continuum they target, and whether environmental factors are considered. Instruments were considered eligible if they represented the patient perspective and measured patient participation in healthcare. The search was limited to articles written in English and published in the last 10 years. We extracted concepts (i.e., patient empowerment, patient participation, and patient-centeredness) based on the framework developed by Castro et al. and outcomes of significance regarding the review questions and specific objectives. The search was conducted in PsycINFO, CINHAL/EBSCO, and PubMed in September 2019 and July 2020. Of 4802 potential titles, 67 studies reported on a total of 45 instruments that met the inclusion criteria for this review. The concept of patient participation was represented most often in these studies. Although some considered the social environment, no instrument was found to incorporate and address the physical environment. Thirteen instruments were generic and the remaining instruments were intended for specific diagnoses or healthcare contexts. Our work is the first to study instruments from this perspective, and we conclude that there is a lack of instruments that measure aspects of the social and physical environment coherently as part of patient participation. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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| 25. |
- Marks, Ellen, 1982, et al.
(author)
-
CD4(+) T-cell immunity in the female genital tract is critically dependent on local mucosal immunization.
- 2011
-
In: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 41:9, s. 2642-53
-
Journal article (peer-reviewed)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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| 26. |
- Mattsson, Johan, et al.
(author)
-
Cholera toxin adjuvant promotes a balanced Th1/Th2/Th17 response independently of IL-12 and IL-17 by acting on Gsα in CD11b(+) DCs.
- 2015
-
In: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 8:4, s. 815-827
-
Journal article (peer-reviewed)abstract
- Despite an extensive literature on the mechanism of action of cholera toxin (CT), we still lack critical information about how the toxin acts as an adjuvant and, especially, which dendritic cells (DCs) are the target cells. Although a T helper type 2 (Th2)-skewing effect of CT is most commonly reported, effective priming of Th17 cells as well as suppression of Th1 responses are well documented. However, the ability of CT to block interferon regulatory factor 8 (IRF8) function and interleukin (IL)-12 production in DCs, which blocks CD8α DC and Th1 cell development, is inconsistent with priming of Th1 and CD8 T cells in many other reports. This prompted us to investigate the adjuvant effect of CT in wild-type, IL-12p40-/-, Batf3-/-, and IL-17A-/- mice and in mice that selectively lack the Gsα target protein for CT adenosine diphosphate (ADP)-ribosylation in DCs. We found that CT promoted Th1 priming independently of IL-12, and whereas Th2 and also Th17 responses were augmented, the gut IgA responses did not require IL-17A. Adjuvanticity was intact in Batf3-/- mice, lacking CD8α(+) DCs, but completely lost in mice with Gsα-deficient CD11c cells. Thus, our data demonstrate that the adjuvant effect requires Gsα expression in CD11b(+) DCs, and that priming of mucosal IgA and CD4 T cells appears unbiased and is independent of IL-12 and IL-17A.Mucosal Immunology advance online publication, 26 November 2014; doi:10.1038/mi.2014.111.
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| 27. |
- Mattsson, Johan, et al.
(author)
-
Complement activation and complement receptors on follicular dendritic cells are critical for the function of a targeted adjuvant.
- 2011
-
In: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 187:7, s. 3641-52
-
Journal article (peer-reviewed)abstract
- A detailed understanding of how activation of innate immunity can be exploited to generate more effective vaccines is critically required. However, little is known about how to target adjuvants to generate safer and better vaccines. In this study, we describe an adjuvant that, through complement activation and binding to follicular dendritic cells (FDC), dramatically enhances germinal center (GC) formation, which results in greatly augmented Ab responses. The nontoxic CTA1-DD adjuvant hosts the ADP-ribosylating CTA1 subunit from cholera toxin and a dimer of the D fragment from Staphylococcus aureus protein A. We found that T cell-dependent, but not -independent, responses were augmented by CTA1-DD. GC reactions and serum Ab titers were both enhanced in a dose-dependent manner. This effect required complement activation, a property of the DD moiety. Deposition of CTA1-DD to the FDC network appeared to occur via the conduit system and was dependent on complement receptors on the FDC. Hence, Cr2(-/-) mice failed to augment GC reactions and exhibited dramatically reduced Ab responses, whereas Ribi adjuvant demonstrated unperturbed adjuvant function in these mice. Noteworthy, the adjuvant effect on priming of specific CD4 T cells was found to be intact in Cr2(-/-) mice, demonstrating that the CTA1-DD host both complement-dependent and -independent adjuvant properties. This is the first demonstration, to our knowledge, of an adjuvant that directly activates complement, enabling binding of the adjuvant to the FDC, which subsequently strongly promoted the GC reaction, leading to augmented serum Ab titers and long-term memory development.
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| 28. |
- Moberg, Jennie, et al.
(author)
-
Review : Young people’s recovery processes from mental health problems – a scoping review
- 2023
-
In: Child and Adolescent Mental Health. - : Wiley. - 1475-357X .- 1475-3588. ; 28:3, s. 393-407
-
Research review (peer-reviewed)abstract
- Background: Recovery from mental illness and mental health problems is relatively well-researched among adults, but evidence that focuses on the recovery experiences of young people and what characterizes it is scarce. With this in mind, this article aims to map out the existing research in order to identify prevailing knowledge about the recovery of young people between the ages of 12 and 25. Method: Drawing on scoping review methodology, this article is based on an analysis of 33 articles conducted in the USA, Australia, and Eur-ope. Results: Our findings reveal that young people express both similar and divergent lines of reasoning about recovery compared with adults. Our findings also indicate that young people often fluctuate in the way they view recovery, and that they thus tend to be ambivalent about what recovery means. Parents usually high-light the importance of professionals facilitating recovery, while care staff problematize the organizational frameworks available as aggravating circumstances for implementing personal recovery. Young people, parents, and care staff consistently describe recovery as a way to, despite lingering problems, enable a satisfying life. Conclusions: Through this review, we outline the need for a more distinct focus on agency and participation in young people’s recovery processes, at the same time as family involvement needs to be further investigated and operationalized.
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| 29. |
- Nedrud, J. G., et al.
(author)
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Subcomponent Vaccine Based on CTA1-DD Adjuvant with Incorporated UreB Class II Peptides Stimulates Protective Helicobacter pylori Immunity
- 2013
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
-
Journal article (peer-reviewed)abstract
- A mucosal vaccine against Helicobacter pylori infection could help prevent gastric cancers and peptic ulcers. While previous attempts to develop such a vaccine have largely failed because of the requirement for safe and effective adjuvants or large amounts of well defined antigens, we have taken a unique approach to combining our strong mucosal CTA1-DD adjuvant with selected peptides from urease B (UreB). The protective efficacy of the selected peptides together with cholera toxin (CT) was first confirmed. However, CT is a strong adjuvant that unfortunately is precluded from clinical use because of its toxicity. To circumvent this problem we have developed a derivative of CT, the CTA1-DD adjuvant, that has been found safe in non-human primates and equally effective compared to CT when used intranasally. We genetically fused the selected peptides into the CTA1-DD plasmid and found after intranasal immunizations of Balb/c mice using purified CTA1-DD with 3 copies of an H. pylori urease T cell epitope (CTA1-UreB3T-DD) that significant protection was stimulated against a live challenge infection. Protection was, however, weaker than with the gold standard, bacterial lysate+CT, but considering that we only used a single epitope in nanomolar amounts the results convey optimism. Protection was associated with enhanced Th1 and Th17 immunity, but immunizations in IL-17A-deficient mice revealed that IL-17 may not be essential for protection. Taken together, we have provided evidence for the rational design of an effective mucosal subcomponent vaccine against H. pylori infection based on well selected protective epitopes from relevant antigens incorporated into the CTA1-DD adjuvant platform.
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| 30. |
- Omokanye, Ajibola, et al.
(author)
-
Clonotypic analysis of protective influenza M2e-specific lung resident Th17 memory cells reveals extensive functional diversity.
- 2022
-
In: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 15, s. 717-729
-
Journal article (peer-reviewed)abstract
- The fate of tissue-resident memory CD4 T cells (Trm) has been incompletely investigated. Here we show that intranasal, but not parenteral, immunization with CTA1-3M2e-DD stimulated M2e-specific Th17 Trm cells, which conferred strong protection against influenza virus infection in the lung. These cells rapidly expanded upon infection and effectively restricted virus replication as determined by CD4 T cell depletion studies. Single-cell RNAseq transcriptomic and TCR VDJ-analysis of M2e-tetramer-sorted CD4 T cells on day 3 and 8 post infection revealed complete Th17-lineage dominance (no Th1 or Tregs) with extensive functional diversity and expression of gene markers signifying mature resident Trm cells (Cd69, Nfkbid, Brd2, FosB). Unexpectedly, the same TCR clonotype hosted cells with different Th17 subcluster functions (IL-17, IL-22), regulatory and cytotoxic cells, suggesting a tissue and context-dependent differentiation of reactivated Th17 Trm cells. A gene set enrichment analysis demonstrated up-regulation of regulatory genes (Lag3, Tigit, Ctla4, Pdcd1) in M2e-specific Trm cells on day 8, indicating a tissue damage preventing function. Thus, contrary to current thinking, lung M2e-specific Th17 Trm cells are sufficient for controlling infection and for protecting against tissue injury. These findings will have strong implications for vaccine development against respiratory virus infections and influenza virus infections, in particular.
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| 31. |
- Rose Mathew, Nimitha, 1987, et al.
(author)
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Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells
- 2021
-
In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:12
-
Journal article (peer-reviewed)abstract
- B cell responses are critical for antiviral immunity. However, a comprehensive picture of antigen-specific B cell differentiation, clonal proliferation, and dynamics in different organs after infection is lacking. Here, by combining single-cell RNA and B cell receptor (BCR) sequencing of antigen-specific cells in lymph nodes, spleen, and lungs after influenza infection in mice, we identify several germinal center (GC) B cell subpopulations and organ-specific differences that persist over the course of the response. We discover transcriptional differences between memory cells in lungs and lymphoid organs and organ-restricted clonal expansion. Remarkably, we find significant clonal overlap between GC-derived memory and plasma cells. By combining BCR-mutational analyses with monoclonal antibody (mAb) expression and affinity measurements, we find that memory B cells are highly diverse and can be selected from both low- and high-affinity precursors. By linking antigen recognition with transcriptional programming, clonal proliferation, and differentiation, these finding provide important advances in our understanding of antiviral immunity.
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| 32. |
- Rosenberg, David, 1957-, et al.
(author)
-
Shared decision making in community mental health services - an evaluation of three self-reporting instruments
- 2017
-
In: Journal of Mental Health. - Abingdon, Oxon : Routledge. - 0963-8237 .- 1360-0567. ; 26:2, s. 142-149
-
Journal article (peer-reviewed)abstract
- Background: Despite the potential impact of shared decision making on users satisfaction with care and quality in health care decisions, there is a lack of knowledge and skills regarding how to work with shared decision making among health care providers.Aim: The aim of this study was to evaluate the psychometric properties of three instruments that measure varied dimensions of shared decision making, based on self-reports by clients, in a Swedish community mental health context.Method: The study sample consisted of 121 clients with experience of community mental health care, and involved in a wide range of decisions regarding both social support and treatment. The questionnaires were examined for face and content validity, internal consistency, test-retest reliability and construct validity.Results: The instruments displayed good face and content validity, satisfactory internal consistency and a moderate to good level of stability in test-retest reliability with fair to moderate construct correlations, in a sample of clients with serious mental illness and experience of community mental health services in Sweden.Conclusions: The questionnaires are considered to be relevant to the decision making process, user-friendly and appropriate in a Swedish community mental health care context. They functioned well in settings where non-medical decisions, regarding social and support services, are the primary focus. The use of instruments that measure various dimensions of the self-reported experience of clients, can be a key factor in developing knowledge of how best to implement shared decision making in mental health services.
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| 33. |
- Schussek, Sophie, et al.
(author)
-
The CTA1-DD adjuvant strongly potentiates follicular dendritic cell function and germinal center formation, which results in improved neonatal immunization
- 2020
-
In: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 13, s. 545-557
-
Journal article (peer-reviewed)abstract
- Vaccination of neonates and young infants is hampered by the relative immaturity of their immune systems and the lack of safe and efficacious vaccine adjuvants. Immaturity of the follicular dendritic cells (FDCs), in particular, appears to play a critical role for the inability to stimulate immune responses. Using the CD21mT/mG mouse model we found that at 7 days of life, FDCs exhibited a mature phenotype only in the Peyer ' s patches (PP), but our unique adjuvant, CTA1-DD, effectively matured FDCs also in peripheral lymph nodes following systemic, as well as mucosal immunizations. This was a direct effect of complement receptor 2-binding to the FDC and a CTA1-enzyme-dependent enhancing effect on gene transcription, among which CR2, IL-6, ICAM-1, IL-1 beta, and CXCL13 encoding genes were upregulated. This way we achieved FDC maturation, increased germinal center B-cell- and Tfh responses, and enhanced specific antibody levels close to adult magnitudes. Oral priming immunization of neonates against influenza infection with CTA1-3M2e-DD effectively promoted anti-M2e-immunity and significantly reduced morbidity against a live virus challenge infection. To the best of our knowledge, this is the first study to demonstrate direct effects of an adjuvant on FDC gene transcriptional functions and the subsequent enhancement of neonatal immune responses.
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| 34. |
- Sharma, Sapna, et al.
(author)
-
A Sensitive Method for Detecting Peptide-specific CD4(+) T Cell Responses in Peripheral Blood from Patients with Myasthenia Gravis
- 2017
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
-
Journal article (peer-reviewed)abstract
- Myasthenia gravis (MG) is an autoimmune neurological disorder typified by skeletal muscle fatigue and most often production of autoantibodies against the nicotinic acetylcholine receptor (AChR). The present study was undertaken to assess the extent of AChR-peptide recognition in MG patients using co-culturing (DC:TC) of autologous monocyte-derived dendritic cells (moDCs) and highly enriched CD4(+) T cells from the blood as compared to the traditional whole peripheral blood mononuclear cell (PBMC) cultures. We found that the DC:TC cultures were highly superior to the PBMC cultures for detection of reactivity toward HLA-DQ/DR-restricted AChR-peptides. In fact, whereas DC:TC cultures identified recognition in all MG patients the PBMC cultures failed to detect responsiveness in around 40% of the patients. Furthermore, reactivity to multiple peptides was evident in DC:TC cultures, while PBMC cultures mostly exhibited reactivity to a single peptide. No healthy control (HC) CD4(+) T cells responded to the peptides in either culture system. Interestingly, whereas spontaneous production of IFN. and IL-17 was observed in the DC:TC cultures from MG patients, recall responses to peptides enhanced IL-10 production in 9/13 MG patients, while little increase in IFN. and IL-17 was seen. HCs did not produce cytokines to peptide stimulations. We conclude that the DC:TC culture system is significantly more sensitive and better identifies the extent of responsiveness in MG patients to AChR-peptides than traditional PBMC cultures.
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| 35. |
- Sjöblom-Hallén, A, et al.
(author)
-
Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant.
- 2010
-
In: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 3:4, s. 374-386
-
Journal article (peer-reviewed)abstract
- Earlier studies have reported on both proinflammatory and anti-inflammatory activities of cholera toxin (CT). As CT is a powerful adjuvant, we were interested in identifying genes with a possible involvement in these functions. A global gene expression analysis in mouse B cells showed that CT regulated <100 annotated genes, which encoded transcription factors, G proteins, cell-cycle regulators, and immunoregulating molecules. Interestingly, CT regulated the expression of the signal transducer and activator of transcription (STAT)3 gene and influenced the level and activation of both isoforms STAT3alpha and STAT3beta, in vitro in a B-cell line and in Peyer's patch (PP) B cells and in vivo in freshly isolated splenic B cells from CT-treated mice. This effect was cAMP dependent and was not seen with CTB. B cells pre-exposed to CT were significantly more susceptible to the activation of STAT3 by interleukin (IL)-6 and IL-10. This exerted a stronger inhibitory effect of IL-10 on lipopolysaccharide (LPS)-stimulated B-cell proliferation and cytokine production (IL-6). Moreover, IgG1 and IgA production induced by LPS and IL-10 were enhanced by the addition of CT to cultures of PP or splenic B cells. This is the first study to provide a molecular mechanism that can reconcile previous findings of proinflammatory and anti-inflammatory effects by CT adjuvant.Mucosal Immunology advance online publication 7 April 2010. doi:10.1038/mi.2010.16.
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| 36. |
- Sundling, Christopher, et al.
(author)
-
CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization.
- 2008
-
In: The Journal of general virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 89:Pt 12, s. 2954-64
-
Journal article (peer-reviewed)abstract
- Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.
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