dc.contributor.advisor | Gürsel, İhsan | |
dc.contributor.author | Bayık, Defne | |
dc.date.accessioned | 2016-05-12T14:08:47Z | |
dc.date.available | 2016-05-12T14:08:47Z | |
dc.date.copyright | 2016-05 | |
dc.date.issued | 2016-05 | |
dc.date.submitted | 2016-05-11 | |
dc.identifier.uri | http://hdl.handle.net/11693/29096 | |
dc.description | Cataloged from PDF version of thesis. | en_US |
dc.description | Includes bibliographical references (leaves 133-171). | en_US |
dc.description | Thesis (Ph. D.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2016. | en_US |
dc.description.abstract | Myeloid-derived suppressor cells (MDSC) play a key role in down-regulating activated T and
NK cells. MDSC are emerging as targets for cancer immunotherapy since they protect tumor
cells from immune elimination. We previously showed that the TLR7/8 agonist R848 and the
TLR2/1 dual agonist PAM3 had opposite effect on the maturation of human monocytic MDSC
(mMDSC). While the former triggered them to differentiation in M1-like macrophages with
pro-inflammatory/anti-tumoricidal capacity, the latter generated immunosuppressive M2-like
macrophages. This work seeks to identify the soluble factors that regulate the differentiation of
mMDSC into macrophages. Our studies reveal that TNFα and M-CSF are essential for mMDSC
to mature into functional M1- and M2-like macrophages, respectively. IL-6 and IL-10 play
secondary roles but when used in combination with TNFα or M-CSF exceed the effects of TLR
agonists. Understanding the response of mMDSC to cytokines should help efforts to direct the
mMDSC maturation to therapeutic benefit.
The finding that PAM3 could induce human mMDSC to mature into M2-like macrophage
triggered us to study the effect of this TLR agonist on other monocyte populations. Our findings
reveal that PAM3 was unique among TLR agonists in generating M2-like macrophages. We
compared the polarizing activity of PAM3 to that of M-CSF. PAM3 was slightly less efficient
than M-CSF in driving maturation of HLA-DR+ monocytes based on phenotypic
characterization and phagocytic ability. Yet macrophages generated by PAM3 or M-CSF were
equally capable of suppressing T cell proliferation. Analysis of gene regulatory networks by
microarray and subsequent validation of the pathways identified by using specific inhibitors
defined the NF-κB – COX-2 axis as playing a primary role. However, PAM3 also induced
monocyte differentiation via an IL-6-dependent pathway that was largely absent from M-CSF driven cultures. Our findings clarified the pathways by which immunosuppressive M2-like
macrophage arise from human monocytes and identify PAM3 as a potential therapeutic
modulator of monocyte differentiation in patients with autoimmune disease.
Extracellular vesicles (EV) are a heterogeneous population of biological nanoscaled particles
that serve as vectors to enhance intercellular communication. In addition to this physiological
role evidence indicates that EV can be harnessed as therapeutic agents for cancer. The major
limitation to EV-based therapeutics is their rapid clearance by the reticuloendothelial system
(RES). To overcome this problem, we sought to reduce macrophage uptake of EV by blocking
scavenger receptors. In vitro results using human and murine cells suggests that inhibiting class
A scavenger receptors selectively impairs EV uptake by monocytes and macrophages. In vivo
studies document reduced liver accumulation and enhanced plasma circulation of i.v. injected
EV after such blockade. These findings provide a strategy for reducing EV uptake by the RES
thereby increasing their targeting and activity. | en_US |
dc.description.statementofresponsibility | by Defne Bayık. | en_US |
dc.format.extent | xxii, 189 leaves : charts, graphics (some color). | en_US |
dc.language.iso | English | en_US |
dc.rights | info:eu-repo/semantics/openAccess | en_US |
dc.subject | Myeloid-derived suppressor cells | en_US |
dc.subject | HLA-DR+ human monocytes | en_US |
dc.subject | M1-like macrophages | en_US |
dc.subject | M2-like macrophages | en_US |
dc.subject | TLR agonists | en_US |
dc.subject | Cytokines | en_US |
dc.subject | Extracellular vesicles | en_US |
dc.subject | Scavenger receptors | en_US |
dc.title | Regulation of human monocyte differentiation into m1- and m2-like macrophages | en_US |
dc.title.alternative | İnsan monositlerinin m1- ve m2-benzeri makrofajlara dönüşümünün düzenlenmesi | en_US |
dc.type | Thesis | en_US |
dc.department | Department of Molecular Biology and Genetics | en_US |
dc.publisher | Bilkent University | en_US |
dc.description.degree | Ph.D. | en_US |
dc.identifier.itemid | B153189 | |
dc.embargo.release | 2018-05-11 | |