Enhanced immunomodulatory applications of nucleic acid encapsulating liposomes

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buir.advisorGürsel, İhsan
dc.contributor.authorErikçi, Erdem
dc.date.accessioned2016-01-08T18:11:28Z
dc.date.available2016-01-08T18:11:28Z
dc.date.issued2009
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.descriptionAnkara : The Department of Moleculer Biology and Genetics and the Institute of Engineering and Science of Bilkent University, 2009.en_US
dc.descriptionThesis (Master's) -- Bilkent University, 2009.en_US
dc.descriptionIncludes bibliographical references leaves 82-90.en_US
dc.description.abstractRecent studies have demonstrated that innate immune system has great ability to discriminate self from non-self through the action of innate immune receptors. The most extensively studied innate immune receptor family is the Toll-like receptors (TLRs). Endosomal/intracellular TLR3, TLR7/8 and TLR9 recognize dsRNA, ssRNA and unmethylated CpG DNA respectively. Upon activation following recognition of nucleic acids by endosomal TLRs, B cells secrete IL6, dendritic cells and macrophages secrete type I IFNs, IL12 and NK cells secrete IFNγ which yields Th1 type immune response. Modulating the immune response to mount such an immune response by TLR ligands are harnessed in medical applications such as anticancer, antiviral, antibacterial therapies, anti-allergen, as vaccine adjuvant and as immunoprotective agents. Promising clinical applications of TLR ligand nucleic acids are hampered due to their premature in vivo digestion by endonucleases and rapid clearance via serum protein absorption leading to limited stability and bioavailability. A powerful tool to overcome this problem can be achieved by encapsulating TLR ligands within liposomes, which increase in vivo stability as well as augment targeting and internalization to relevant innate immune cells. In this study we aimed to establish the most immunostimulatory liposome type encapsulating or coencapsulating CpG ODN and pIC. Five different liposomes possessing different physicochemical properties were prepared and their immunostimulatory potential when nucleic acid TLRs are loaded, were assessed. Following stimulation of splenocytes with combinations of these liposome types we have observed that neutral, anionic and stealth liposome encapsulating D-ODN, led to a dose dependent significantly higher IFNγ production over free counterpart. Stealth liposome encapsulating pIC induced both IL6 and IFNγ 10 and 250 fold respectively over free pIC. Neutral and anionic liposome coencapsulating D-ODN with pIC were very strong type 1 IFN as well as Th1 cytokine inducers both in vitro and ex vivo. Then, we immunized B6 mice with anionic liposome coencapsulating D-ODN and OVA to establish the immuno-adjuvant properties of liposome formulations in vivo. We assessed primary and secondary anti-OVA IgG subclass responses of mice. Results strongly implicated that even after primary immunization, we could obtain significantly higher anti-OVA IgG and IgG2a response over OVA mixed D-ODN group. After booster injection, 22 fold more IgG, 26 fold more IgG1 and 13 fold more IgG2a were obtained compared to free group. Our findings demonstrated that when simultaneous delivery of adjuvant (D-ODN) and antigen (OVA) within a proper depot system is given to a host, very potent antigen specific immunity is achieved. This knowledge will pave the way to design of novel effective vaccine adjuvants.en_US
dc.description.degreeM.S.en_US
dc.description.statementofresponsibilityErikçi, Erdemen_US
dc.format.extentxvi, 93 leaves, illustrations, graphicsen_US
dc.identifier.urihttp://hdl.handle.net/11693/14955
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectTLRen_US
dc.subjectIgGen_US
dc.subjectcytokineen_US
dc.subjectvaccinationen_US
dc.subjectliposomeen_US
dc.subjectdsRNAen_US
dc.subjectCpG DNAen_US
dc.subject.lccQR185.2 .E75 2009en_US
dc.subject.lcshNatural immunity.en_US
dc.subject.lcshImmunity, Natural--Physiology.en_US
dc.subject.lcshNucleic acids.en_US
dc.subject.lcshAutoimmune diseases.en_US
dc.subject.lcshAutoimmunity.en_US
dc.subject.lcshDNA.en_US
dc.subject.lcshLiposomes.en_US
dc.titleEnhanced immunomodulatory applications of nucleic acid encapsulating liposomesen_US
dc.typeThesisen_US

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Dept. of Molecular Biology and Genetics - Master's degree