Browsing by Subject "Suppressive ODN A151"

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Open Access
Elucidating immunomodulatory effects of telomeric repeat mimicking synthetic A151 oligodeoxynucleotide on immune cell transcriptome
(2019-09) Yazar, Volkan
Recent evidence revealed that DNA is beyond just the blueprint of life; it is also involved in immunomodulation. Unmethylated Cytosine-phosphate-Guanine (CpG) motifs of prokaryotic DNA stimulate immune response by interacting with Toll-like receptor 9 (TLR9). This interaction is mimicked using synthetic oligodeoxynucleotides (ODN) bearing similar DNA motifs to boost vaccinedriven immune response in human. Conversely, mammalian telomeric ends expressing TTAGGG repeats suppress immune response and contribute to fine-tuning of delicate immune balance. In this respect, suppressive ODN A151 with such G-rich telomeric repeats has proven useful in downregulating immune response; an overly active immune response is just as harmful to the host, as in the case of autoimmune disorders. Both CpG ODN and A151 are currently under preclinical/clinical trials with the aim of averting or medically treating a wide range of conditions from cancer to infectious disease or from autoimmune to autoinflammatory conditions. Contrary to CpG ODN, A151 literature is very limited and its modus operandi at gene level remains more of a mystery. Additionally, the degree, duration and breath of A151-induced alterations in immune transcriptome appear partially understood. Given the medical potential A151 holds for immunosuppressive therapy in human as a “self-molecule”, understanding the underlying molecular mechanisms via which A151 operates is invaluable. Toward this end, we attempted to uncover the unidentified features lying behind A151 ODNs immunosuppressive effects on immune cell transcriptome using a combined analysis approach of microarray data in this thesis. We demonstrated for the first time that A151 ODN deprives the cells energy by ceasing cellular uptake of fundamental molecules into the immune cells after derailing the entire intracellular trafficking. Putting it another way, A151 does not directly act on immune system cells but actually suffocates the cells by messing with intracellular trafficking, thereby blocking cellular uptake of fundamental molecules like glucose and glutamine. As such, immune suppression is just an indirect consequence of this larger cellular chaos. Our results indicated that this phenomenon occurs independent of CpG ODN stimulation of the cells and in a timely manner. Most, if not all, regulators of intracellular trafficking, vesicle signaling, and membrane protein transportation were found downregulated after incubation of cells with A151 at a physiologically relevant concentration, as well, implying full-blown entry to this intracellular turmoil at cellular level. The A151 effect on immune transcriptome was not just restricted to setting off a chaos for intracellular dynamics; novel long non-coding RNAs (lncRNAs) with immunometabolic activities were identified within the scope of this study among elements potentially regulated by A151, such as Lncpint, Malat1 and H2-T10 just to name a few. The involvement of lncRNAs in immune regulation is a well-documented phenomenon. Finally, our data showed that as an epiphenomenon of the intracellular turmoil mentioned above A151 has a deep impact in immune cells on mTOR network, the cardinal network of cellular energetics, growth, proliferation, and survival. A major shift in expression profile of relevant genes, i.e. downregulation of many activators of mTOR signaling along with core mTOR components, was validated on the benchtop after different layers of experimental validation using a wide range of marker genes and functional assays, reflecting A151’s ability to vastly shape dynamics of metabolism in favor of a metabolically inert state in macrophages and in B-cells. This knowledge will expand the breadth of A151 therapy in the clinics.
Open Access
Therapeutic approaches to the prevention of liver fibrosis and cancer progression
(2015-08) Aydın, Muammer Merve
In our previous studies on liver regeneration, we demonstrated that following partial hepatectomy (PH) FLT3 contributes cellular proliferation that provides a basis for liver regeneration. Moreover, we were able to suggest a potential role for FLT3 in hepatocarcinogenesis for the first time. Therefore, we further investigated the effect of FLT3 inhibition on the invasiveness and aggressiveness of hepatocarcinogenesis. Our findings were parallel to our previous results supporting the contribution of FLT3 in hepatocarcinogenesis. Thus, we are presenting FLT3 as a novel candidate for the diagnosis and treatment of HCC. We also focused on liver fibrosis since it is the initial wound healing response generated by the liver against damaging insults. Liver fibrosis is a reversible process, but if its progression is not prevented it might turn into cirrhosis and end up with HCC. Toll-like receptors (TLRs) have been reported to contribute to this fibrotic response generated in the liver resulting from the activating effects of various danger ligands. We show that using suppressive oligodeoxynucleotide (ODN) A151 might control TLR dependent immune activation that takes place after the induction of liver fibrosis. Our results show that suppressive ODN A151 administration has a negative effect on αSMA expression and collagen accumulation, which are the major events taking place during liver fibrogenesis. Additionally, this suppressive effect of suppressive ODN A151 was revealed to be systemic. Splenocytes of suppressive ODN A151 administered mice showed different cytokine secretion patterns and antigen presenting cell (APC) function after being stimulated with various TLR ligands. These findings suggested us that using suppressive ODN might be a rational and novel approach to control the liver fibrogenesis and even prevent its progression into cirrhosis reducing the number of liver transplantations needed by the patients. Finally, we focused on HSPs, some of which are also known to activate TLR signaling. Additionally, HSP27 has a role in actin cytoskeleton organization and controlling cellular motility, which are among the events that take place in liver fibrogenesis. Therefore, for the first time we present preliminary data on the potential role of HSP27 in liver fibrosis and quercetin treatment as a therapeutic approach due to its HSP27 and αSMA expression changing effects.