Ankara : The Department of Molecular Biology and Genetics and the Graduate School Engineering and Science of Bilkent University, 2013.Thesis (Master's) -- Bilkent University, 2013.Includes bibliographical references leaves 71-86.CpG ODNs are potent immunotherapeutic agents. In human, two major
classes of CpG ODNs were shown to induce differential immune activation. D
ODNs are strong IFNα inducers, thus promising antiviral agents, whereas K
ODNs are effective against bacterial infections. However, their effects cannot be
combined. When K and D type ODNs are used simultaneously, K ODN cancels
D specific effect, a phenomenon known as K and D ODN dichotomy. The prime
reason for this counter acting K ODN action was subcellular compartmentalization
of K type CpG ODNs upon internalization. Besides, CpG ODNs have labile
nature. When investigated in clinical trials, these nucleic acid based ligands
are eliminated upon administration and displayed limited bio-availability due
to nuclease digestion. Hence, efforts to protect in vivo performance, and
increase stability and accumulation near target cells became a crucial task.
Liposome technology offers a simple and mild approach to harbor these ODNs
within membrane bilayers and protect them. We also reasoned that, if we use
liposomes that alter subcellular fate of K and D ODNs, we can retain both
K and D effect when liposomal ODNs are co-administered and the breadth of
immunotherapeutic spectrum could be improved. This thesis was designed to
understand and characterize different types of CpG ODNs loaded into different
liposomes and aimed to determine their activities in different in vitro and in
vivo settings. Our results revealed that when two different classes of clinically
important CpG ODNs were encapsulated within proper liposome types, it is
possible to recapitulate both K and D type ODN effect in PBMCs. Furthermore,
in a vaccine model against H. felis, although initially did not induce significantly
higher anti H.felis immunity, liposomal CpG ODNs improved persisting antibody
levels for extended periods compared to free counterparts. Collectively, our results
demonstrate that this platform allows more effective in vivo utilization of CpG
ODNs and can be formulated to develop more efficient means to combat several
health problems, ranging from cancer to allergy.Dereli, İhsanM.S
