Targetting innate immune responses to improve vaccine strategies
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1 Research Collection Doctoral Thesis Targetting innate immune responses to improve vaccine strategies Author(s): Mohanan, Deepa Publication Date: 2013 Permanent Link: Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library
2 DISS. ETH NO TARGETTING INNATE IMMUNE RESPONSES TO IMPROVE VACCINE STRATEGIES A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences presented by DEEPA MOHANAN Master of Science, National University of Singapore Born 7 th April 1981 Singaporean accepted on the recommendation of Professor Manfred Kopf, examiner Professor Bruno Gander, co-examiner Professor Martin Bachmann, co-examiner PD Dr. Thomas Kündig, co-examiner 2013
3 1. Summary 1 P age
4 Vaccines have had a major impact on mankind since the introduction of a smallpox vaccine by Edward Jenner in Despite their great success, vaccines have not yet shown their full potential. There are no effective vaccines for a number of chronic diseases such as AIDS, tuberculosis (TB), and malaria simply because our working knowledge of each disease s immunopathogenesis is poor and the pathogen-host relationships are complex. A successful vaccine should be able to induce life-long protective B and/or T cell responses. However, to initiate adaptive immunity, the vaccine needs to trigger the innate immune system as well. Dendritic cells (DCs) have been identified as the key antigen presenting cells (APCs) that are needed for adaptive immunity, particularly for T cell responses. DCs express a myriad of pathogen-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) as well as host derived danger signals known as damageassociated molecular patterns (DAMPs). It is through the engagement of these receptors that is crucial for activation of the innate immune system. To help design better vaccines for tomorrow, it is therefore important to understand how pathogens negatively manipulate the activation of the innate immune system. Moreover, by better targeting antigen and adjuvant to DCs we might be able to maximise the potential of inducing a desirable immune response. To improve the current TB vaccine Bacille Calmette Guérin (BCG), we created a mutant strain (BCGΔzmp) that is defective in expressing a zinc-metalloprotease (ZMP-1). This mutant has been shown previously to induce increased phagosome maturation as well as inflammasome activation. It has also been shown to be more immunogenic in mice. A goal of this thesis was to decipher the mechanisms by which ZMP-1 was dampening the activation of DCs, with a special focus on inflammasome activation and toll-like receptor (TLR)-signalling. Activation of the inflammasomes results in the secretion of proinflammatory cytokines IL- 1α/β and the importance of IL-1α/β in host s defence against TB have previously been shown by others. We observed a time-dependent inhibitory influence of ZMP-1 on the secretion of IL-1α/β. Although the secretion of IL-1β was completely dependent on the canonical inflammasome components NLRP3 and ASC, it was only partially dependent on caspase 1/11. Secretion of IL-1α, on the other hand was not dependent on the inflammasome. The increased IL-1α/β secretion by BCGΔzmp was dependent on phagocytosis, acidification of phagosomes as well as signalling via a PRR, TLR2 and its adapter protein myeloid differentiation primary response 88 (MyD88). On the other hand, in the absence of TLR4 or its adapter protein, TIRdomain-containing adapter-inducing interferon-β (TRIF), infection with BCGwt or 2 P age
5 BCGΔzmp led to higher levels of IL-1β being secreted than from wild-type BMDCs. In fact the differences in IL-1β secretion between BCGwt and BCGΔzmp were abrogated in the absence of TLR4 or TRIF. This suggests that BCGwt signals primarily via TLR4-TRIF leading to a negative-feedback that inhibited its ability to secrete IL-1β, whereas BCGΔzmp signals via TLR2/MyD88. Gene expression analysis supported this hypothesis as expression of Interferon regulatory factor 3 (Irf3) (a transcriptional factor acting downstream of TLR4- TRIF signalling) and its downstream effectors were upregulated in the presence of BCGwt. These in vitro data were confirmed in vivo. BCGΔzmp caused increased recruitment of inflammatory monocytes by a caspase-1/11 dependent mechanism in mice. In addition of activation of the innate immune system, vaccine delivery to lymphoid organs is equally important for driving adaptive immune responses. In the next study, we were concerned with this question and tested the influence of administration routes on the immunogenicity of three selected vaccine formulations; liposomes, nanoparticles and microspheres. Our goal was to compare the immunological outcomes after immunisation with a particle-based vaccine formulation via one of the three commonly used administration routes (subcutaneous, intra-dermal and intra-muscular) and whether the addition of adjuvants; Trehalose-6,6-dibehenate (TDB) for liposomes, lipopolysaccharide (LPS) for nanoparticles and CpG for microspheres would affect the observed immune responses. We found that the route of immunization as well as adding an appropriate adjuvant was more important for the induction of IgG2a than IgG1 responses. Microspheres showed more rapid and higher IgG2a responses in the presence of CpG. In contrast, TDB or LPS only enhanced the kinetics but not magnitude of liposome- or nanoparticles-induced IgG2a responses respectively. In general, subcutaneous administration of all formulations induced poor IgG2a responses whereas intramuscular and intradermal administrations both induced higher responses. Sterility is an important practical aspect of vaccines. In a third study, we investigated whether immunogenicity of a protein encapsulated within poly (D, L-lactide-co-glycolide) (PLGA) microspheres would be affected by gamma-irradiation, a more cost-effective and easier alternative to aseptic production of microspheres. Through in vitro and in vivo studies, we were able to demonstrate that protein encapsulated within microspheres was not affected by gamma-irradiation. In contrast, free protein immunogenicity was affected by gammairradiation. 3 P age
6 2. Zusammenfassung 4 P age
7 Seit der Einführung der Pockenimpfung durch Edward Jenner im Jahr 1796 haben Impfungen eine grosse Bedeutung für die Menschheit. Trotz ihres durchschlagenden Erfolgs haben Impfstoffe ihr volles Potential noch nicht entfaltet. Es gibt keine wirksamen Impfungen gegen chronische Erkrankungen wie beispielsweise AIDS, Tuberkulose oder Malaria, weil unser Wissen über die Immunpathologie dieser Krankheiten bisher noch mangelhaft ist und weil die Wirt-Pathogen-Interaktionen komplex sind. Ein erfolgreicher Impstoff sollte eine lebenslang schützende B- und/ oder T-Zell-Antwort induzieren können. Um jedoch eine adaptive Immunantwort zu induzieren, müssen die Vakzine zuerst das angeborene Immunsystem aktivieren. Dabei spielen dendritische Zellen (DC) eine Schlüsselrolle. Sie sind die Antigen präsentierenden Zellen, speziell bei der Induktion einer T-Zell-Antwort. DCs exprimieren eine grosse Anzahl an Pathogenerkennenden Rezeptoren, welche sowohl Pathogen-assoziierte molekulare Strukturen (PAMPs) als auch körpereigene Gefahrensignale, sogenannte Schaden-induzierte molekulare Strukturen (DAMPs), erkennen. Durch das Binden dieser Strukturen an die Rezeptoren wird das angeborene Immunsystem aktiviert. Um zukünftig bessere Impfstoffe zu entwickeln, ist es deshalb notwendig zu verstehen wie Pathogene die Aktivierung des angeborenen Immunsystems verhindern. Zusätzlich würde eine verbesserte Zuführung von Antigen und Adjuvans zu den dendritischen Zellen die gewünschte Immunantwort verstärken. Um den bestehenden BCG-Impstoff zu verbessern, haben wir einen mutierten BCG-Stamm generiert, welcher eine Zink-Metalloprotease (ZMP-1) nicht exprimiert. Der so mutierte Stamm induzierte die Reifung von Phagosomen und die Aktivierung des Inflammasoms; zusätzlich zeigte er eine verstärkte Immunogenität in einem Mausmodell. Ein Ziel dieser Arbeit war es zu analysieren durch welchen Mechanismus ZMP-1 die Aktivierung von DCs abschwächt; dabei standen die Inflammasomaktivierung und die Toll-like receptor (TLR)- Signalwege im Fokus. Die Aktivierung des Inflammasoms führt zur Sekretion der proinflammatorischen Zytokine IL-1α und IL-1β.Vor Kurzem wurde gezeigt, dass IL-1α/β eine tragende Rolle bei der Abwehr gegen Tuberkulose spielt. Wir konnten einen zeitabhängigen inhibierenden Effekt von ZMP-1 auf die Sekretion von IL- 1α/β beobachten. Die Sekretion von IL-1β war vollständig von den Inflammasomkomponenten NLRP3 und ASC, jedoch nur teilweise von Caspase-1/11 abhängig. Die Sekretion von IL-1α war dagegen unabhängig vom Inflammasom. Die erhöhte 5 P age
8 Sekretion von IL-1α/β bei Infektionen mit dem mutierten BCGΔzmp-Stamm war von Phagozytose, der Reifung der Phagosomen und von TLR2- und myeloid differentiation primary response 88 (MyD88)-Signalwegen abhängig. Andererseits sekretierten BCGwtund BCGΔzmp-Stämme in der Abwesenheit von TLR4 oder dessen Adaptor TIR-domaincontaining adapter-inducing interferon-β (TRIF) höhere Mengen an IL-1α/β als wildtyp- BMDCs. Tatsächlich war der Unterschied in der IL-1α/β Sekretion zwischen BCGwt und BCGΔzmp in der Abwesenheit von TLR4 oder TRIF nicht mehr messbar. Das legt die Vermutung nahe, dass BCGwt bevorzugt die TLR4-TRIF-Signalwege nutzt, was dazu führt, dass die Fähigkeit des Stamms, die Sekretion von IL-1α/β zu induzieren, inhibiert wird. Im Gegensatz dazu nutzt BCGΔzmp bevorzugt die TLR2-MyD88-Signalwege. Expressionsanalysen unterstützen diese Hypothese, da die Expression von Irf3 (ein Effektorprotein in der TLR4-TRIF-Signalachse) und dessen weiteren Effektoren bei Infektionen mit BCGwt erhöht war. Diese in vitro-daten konnten auch in vivo bestätigt werden. Infektionen mit BCGΔzmp führten durch einen Caspase-1-abhängigen Mechanismus zu einer erhöhten Einwanderung von inflammatorischen Monozyten. Zusätzlich zur Aktivierung des angeborenen Immunsystems ist die Zuführung des Impfstoffs zu den Lymphorganen ein wichtiger Faktor für die Aktivierung des adaptiven Immunsystems. Deswegen untersuchten wir in einem nächsten Projekt, inwiefern die Art der Verabreichung die Immunogenität eines Impfstoffs beeinflusst. Dafür wurden drei Impfstoffformulierungen gewählt, Liposomen, Nanopartikel und Mikrosphären. Unser Ziel war es einerseits, die immunologischen Konsequenzen zu vergleichen welche aus der Immunisierung mit einem partikelbasierten Impfstoff durch einen der drei normalerweise benutzten Verabreichungswege (subkutan, intradermal oder intramuskulär) resultieren; andererseits wollten wir untersuchen, ob die Beigabe von Adjuvantien: Trehalose-6,6-dibehenat (TDB) für Liposomen, Lipopolysaccharid (LPS) für Nanopartikel und CpG für Mikrosphären, die beobachtete Immunantwort verändert. Wir fanden heraus, dass sowohl der Verabreichungsweg als auch die Beigabe des passenden Adjuvans wichtiger für die Induktion von IgG2a- als von IgG1-Antworten war. Mikrosphären induzierten eine schnellere und erhöhte IgG2a-Antwort, wenn das Adjuvans CpG beigegeben wurde. Im Gegensatz dazu erhöhten TDB oder LPS nur die Kinetik, nicht aber die Stärke von Liposomen- oder Nanopartikel-induzierten IgG2a-Antworten. Generell resultierte eine subkutane Verabreichung aller Impfstoff-Formulierungen in einer schwächeren IgG2a-Antwort als eine intramuskuläre oder intradermale Verabreichung. 6 P age
9 Sterilität ist ein wichtiger praktischer Aspekt von Vakzinen. In einem dritten Projekt untersuchten wir, ob die Immunogenität eines Proteins, das in einer PLGA Mikrosphäre eingekapselt wurde, durch Gammastrahlen beeinflusst wird. Bestrahlung mit Gammastrahlen ist eine kosteneffektive und einfache Alternative aseptische Mikrosphären herzustellen. Wir konnten sowohl mit in vitro- als auch mit in vivo-experimenten zeigen, dass ein in Mikrosphären eingekapseltes Protein durch Gammastrahlen nicht beeinflusst wird. Im Gegensatz dazu wurde die Immunogenität eines nicht eingekapselten Proteins durch die Bestrahlung beeinflusst. 7 P age
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