Immunotherapeutic applications of nucleic acid based tlr agonists and antagonists
Author(s)
Advisor
Gürsel, İhsanDate
2014Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
Recent evidence suggests that genetic material is not just the blueprint of life.
Depending on the type of the source that genomic material is extracted or the type of
motif that DNA harbors DNA could be immunostimulatory or immunosuppressive to
innate immune system cells. Unmethylated CpG motifs, from bacterial genome is
recognized by TLR9 expressing cells as “non-self” and initiates an orchestrated
immune activation characteristics of Th1-biased immunity. Conversely, mammalian
genome rich in G-runs motifs, such as telomeric ends expressing TTAGGG repeats
downregulate Th1-biased immune responses and contributes to restore over
exuberant immune response. Several TLR agonists/antagonists candidates are
currently under preclinical/clinical trials to prevent or treat cancer, infectious disease,
allergic disorders and autoimmune or autoinflammatory diseases. In this thesis, we
attempted to broaden the application of nucleic acid based TLR therapy by
investigating their beneficial effects either as vaccine adjuvants against Foot and
Mouse Disease or to test as immunosuppressive agents that may control autoimmune
uveitis. We showed that an immunosuppressive ODN namely A151 downregulated
severity of an established animal model of uveitis, endotoxin induced uveitis (EIU),
up to more than 60% histologically, or more than 80% based on cytokine production
such as MIP3α, IL6, IFNγ from uveitic animals. In order to compare effects of this
biological immunosuppressive agent, next we studied effects of a broad-spectrum
immunosuppressive drug, namely cyclosporine A in an emulsion form, commercially
known as Restasis™. Our results indicated that Restasis™ had significantly lower
capacity to reduce disease severity and downregulate in vivo chemokine or cytokine
levels compared to A151. The second theme of this thesis was to demonstrate
effective utilization of CpG ODN as an immunostimulatory agent. The adjuvant
effect of CpG ODN 1555-PS in Foot and Mouth Disease (FMD) vaccine
formulations were tested. In this study, CpG ODNs were formulated either with
commercially used monovalent vaccine or mixed with free Serotype-O Ag. Data
suggested that, in mice, inclusion of CpG ODN as an adjuvant, spared the Ag by 6
fold and the vaccine dependent virus neutralization titers were not only higher but
also long lasting compared to commercial monovalent vaccine. CpG inclusion in the
FMD vaccine helped to generate 1.5-2 fold more cell mediated immunity 24 h after
booster injection. Implicating that virus infection could be more effectively
controlled by the novel approach. In the last part of this thesis, effects of CpG ODNs
as prophylactic agents for newborn broiler chicken were tested in vivo. Our results
suggested that CpG ODN pretreatment not only significantly reduced mortality rates
(> 2.0 %) but also contributed to growth performance of these industrially important
animals. We demonstrated that nucleic acid based agonists and antagonists might be of great potential to be developed as therapeutic agents either in the clinic or forcontrolling health of industrially important animals.
Keywords
Innate immunityTLR
uppressive ODN A151
Cyclosporine A EIU
FMD
vaccine
adjuvant
chicken
prophylactic agent