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Mucosal immunity against mycobacterial infection
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Immunology)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis aimed to the identification of immune biomarkers of mycobacterial infection for better diagnosis of tuberculosis (TB) and also focused on new vaccination strategies with a particular emphasis on the immune responses in the respiratory tract using murine models.

Since the lung is the natural habitat for the M. tuberculosis, we reasoned that immune responses detected locally in the lungs would be good correlates of infection (Paper I). Likewise, immune responses induced in the respiratory tract following immunization would be more effective against mycobacterial infection. We showed that cytokines (IL-12, TNF, and IFN-γ) and cytokine receptors (sTNFR1 and sTNFR2) together with specific antibodies in the respiratory tract correlated better with the bacterial burden in the organs. In Paper II, we investigated the role of the BCG vaccination as a priming vaccine in a heterologous prime-boost immunization protocol. The results showed that the neonatal BCG vaccination primed the immune system for a relevant antigen and showed a generalized adjuvant effect. Using this immunization protocol, protective immune responses in the lungs were generated independently of the route used for the booster immunization. In Paper III, We showed that exposure to mycobacterial antigens during the gestational period led to antigen transportation from the mother to the fetus and this resulted in an early priming of the fetal immune system. Immunization with the same antigen during the postnatal life increased antigen-specific recall IFN-γ responses and protection against infection. We examined the role of innate immunity for the induction of acquired immune responses upon immunization with mycobacterial antigens using TLR2 deficient mice (Paper IV). Our data indicated that suboptimal innate immune responses in the TLR2-/- mice might compromise the induction of acquired immune responses.

Overall, the current findings suggested that a better understanding of the mucosal immunity would be useful for the improvement of diagnostic procedures and the development of efficient vaccines against TB.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University , 2010. , 93 p.
Keyword [en]
Mucosal immunity, Vaccination, Diagnosis, Mycobacterial infection
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-39170ISBN: 978-91-7447-081-9 (print)OAI: oai:DiVA.org:su-39170DiVA: diva2:319036
Public defence
2010-06-18, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: ManuscriptAvailable from: 2010-05-31 Created: 2010-05-12 Last updated: 2018-01-12Bibliographically approved
List of papers
1. Increased levels of immunological markers in the respiratory tract but not in serum correlate with active pulmonary mycobacterial infection in mice
Open this publication in new window or tab >>Increased levels of immunological markers in the respiratory tract but not in serum correlate with active pulmonary mycobacterial infection in mice
Show others...
2009 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15, no 8, 777-786 p.Article in journal (Refereed) Published
Abstract [en]

Immunological tests for the diagnosis of tuberculosis (TB) have relied mostly on detection of immune markers in serum or release of cytokines by mononuclear cells in vitro. These tests, although useful, sometimes fail to discriminate between active infection and contact with mycobacteria or vaccination. TB is primarily a disease of the lung, and therefore identification of immunological markers in the respiratory tract will be more likely to reflect the infection status or disease activity. In this study, it is demonstrated that active infection of mice with Mycobacterium bovis bacille Calmette-Guérin (BCG), but not exposure to heat-killed BCG, induced production of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) or soluble tumour necrosis factor receptors (sTNFRs) locally in the lungs, as detected in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between bacterial growth in the lung and levels of sTNFRs, and to some extent IL-12 and IFN-gamma, in BAL fluid. Furthermore, sTNFR levels increased significantly in BAL fluid after reactivation of controlled infection with dexamethasone, and this correlated with increased bacterial growth in the lungs. Finally, infection, but not exposure to non-replicating mycobacteria, induced specific IgG and IgA in BAL fluid. Elevated levels of all biomarkers measured were also detected in the serum, but correlation with infection was not as clear as in the case of BAL fluid. Taken together, the detection of sTNFRs and mycobacterium-specific antibodies, especially IgA, locally in the lungs could be used as immunological markers for the diagnosis of TB.

Keyword
Antibodies, cytokine receptors, cytokines, lung infection, mycobacterial infection
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-39172 (URN)10.1111/j.1469-0691.2009.02734 (DOI)
Available from: 2010-05-12 Created: 2010-05-12 Last updated: 2018-01-12Bibliographically approved
2. Neonatal vaccination with Mycobacterium bovis BCG: potential effects as a priming agent shown in a heterologous prime-boost immunization protocol
Open this publication in new window or tab >>Neonatal vaccination with Mycobacterium bovis BCG: potential effects as a priming agent shown in a heterologous prime-boost immunization protocol
2009 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 30, 4038-4046 p.Article in journal (Refereed) Published
Abstract [en]

In general prime-boost immunization including Mycobacterium bovis bacille Calmette-Guérin (BCG) as a priming agent has been a recent successful strategy in animal models. However, the effects of BCG as a priming vaccine have not been investigated systematically. Thus, we modelled a heterologous prime-boost immunization in mice with BCG administered at the neonatal period and mycobacterial heparin-binding hemagglutinin (HBHA) at adult ages. Mice were challenged with a high dose of BCG (10(7) colony forming units) via intranasal (i.n.) route. We addressed whether the route of administration and addition of adjuvants could be of importance in HBHA-immunizations while animals were primed with BCG. Our results showed that prime-boost immunization induced significantly higher levels of protection in animals compared to the group vaccinated with BCG alone. Most importantly, the levels of protection were comparable between the i.n. and subcutaneous (s.c.) boostings with native (n) HBHA and the coadministration of adjuvant was not necessary. Moreover, priming with BCG improved also the protection promoted by the recombinant form of HBHA, even if to a lower degree to that observed after nHBHA boosting. In general, vaccination with BCG prior to the HBHA administration was found to contribute in two ways: it primed the immune system and provided adjuvant effect. We discuss the several outcomes following neonatal BCG priming and HBHA boosting for better protection against tuberculosis

Keyword
BCG vaccine; Neonates; Heparin-binding hemagglutinin
Identifiers
urn:nbn:se:su:diva-39195 (URN)10.1016/j.vaccine.2009.04.027 (DOI)000267581500015 ()
Available from: 2010-05-12 Created: 2010-05-12 Last updated: 2017-12-12Bibliographically approved
3. Influence of maternal gestational treatment with mycobacterial antigens on postnatal immunity in an experimental murine model
Open this publication in new window or tab >>Influence of maternal gestational treatment with mycobacterial antigens on postnatal immunity in an experimental murine model
2010 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 3, e9699- p.Article in journal (Refereed) Published
Abstract [en]

It has been proposed that the immune system could be primed as early as during the fetal life and this might have an impact on postnatal vaccination. Therefore, we addressed in murine models whether gestational treatment with mycobacterial antigens could induce better immune responses in the postnatal life. METHODS/FINDINGS: BALB/c mice were treated subcutaneously (s.c.) at the second week of gestation with antigen (Ag)85A or heparin-binding hemagglutinin (HBHA) in the absence of adjuvant. Following birth, offspring mice were immunized intranasally (i.n.) with the same antigens formulated with the adjuvant cholera toxin (CT) at week 1 and week 4. One week after the last immunization, we assessed antigen-specific recall interferon gamma (IFN-gamma) responses by in vitro restimulation of lung-derived lymphocytes. Protection against infection was assessed by challenge with high dose Mycobacterium bovis Bacille Calmette-Guérin (BCG) given i.n. We found that recall IFN-gamma responses were higher in the offspring born to the treated mother compared to the untreated-mother. More importantly, we observed that the offspring born to the treated mother controlled infection better than the offspring born to the untreated mother. Since the gestational treatment was done in absence of adjuvant, essentially there was no antibody production observed in the pregnant mice and therefore no influence of maternal antibodies was expected. We hypothesized that the effect of maternal treatment with antigen on the offspring occurred due to antigen transportation through placenta. To trace the antigens, we conjugated fluorescent nanocrystals with Ag85A (Qdot-ITK-Ag85A). After inoculation in the pregnant mice, Qdot-ITK-Ag85A conjugates were detected in the liver, spleen of pregnant females and in all the fetuses and placentas examined. CONCLUSION: The fetal immune system could be primed in utero by mycobacterial antigens transported through the placenta.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-39175 (URN)10.1371/journal.pone.0009699 (DOI)000275621000016 ()20300629 (PubMedID)
Available from: 2010-05-12 Created: 2010-05-12 Last updated: 2017-12-12Bibliographically approved
4. Immunization with mycobacterial antigens: a role for innate immunity in antigen presentation
Open this publication in new window or tab >>Immunization with mycobacterial antigens: a role for innate immunity in antigen presentation
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

We have found that toll-like receptor (TLR) 2 was important in the control of mycobacterial infection in the lungs. However, it is unclear how the TLR2-mediated innate immunity contributes to the development of acquired immune responses upon immunization with mycobacterial antigens. In the present study, we addressed this issue by immunizing TLR2 knockout (TLR2-/-) and wild-type (WT) mice with mycobacterial 19kDa (TLR2 ligand) or Ag85A (non-TLR2 ligand) antigens. We compared both humoral and cellular immune responses in the two mouse strains. Interferon gamma (IFN-g) responses were measured in the culture supernatants after in vitro restimulation of spleen cells with antigen alone, antigen-pulsed bone marrow derived macrophages (BMMAg) or BCG-infected BMM (BMMBCG). We found that the magnitude of antigen-specific antibody responses in serum was comparable in the two mouse strains. With regard to the two antigens, immunization with 19kDa induces more Th1 type immune responses compared to the immunization with Ag85A. We observed differences in the response of the two strains upon restimulation with antigen alone or with BMMAg regarding 19kDa. Recall IFN-g responses to 19kDa were significantly lower in the TLR2-/- mice compared to the WT mice. Interestingly, IFN-g responses to BMMBCG were similar in both strains probably due to the fact that BCG targets other cell surface molecules. The expression of CD86 in the BMMBCG was found to be TLR2-independent whereas in the BMMAg it was TLR2-dependent.

Altogether, results from this study indicate that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigens (TLR2 dependent or independent) used for immunization. We discuss the relevance of innate immunity for the induction of acquired immune responses.

Identifiers
urn:nbn:se:su:diva-39178 (URN)
Available from: 2010-05-12 Created: 2010-05-12 Last updated: 2010-05-31

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