東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Novel protocols to induce tolerance ...

Chakhtoura, Marita.

FindBook

Google Book

Amazon

博客來

Novel protocols to induce tolerance to solid organ transplants.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Novel protocols to induce tolerance to solid organ transplants./
作者:	Chakhtoura, Marita.
面頁冊數:	252 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
Contained By:	Dissertation Abstracts International77-10B(E).
標題:	Immunology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10111290
ISBN:	9781339744995

Novel protocols to induce tolerance to solid organ transplants.
Chakhtoura, Marita.

Novel protocols to induce tolerance to solid organ transplants. - 252 p.

Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.

Thesis (Ph.D.)--Temple University, 2016.

Dendritic cells (DCs) are the sentinels of the immune system. They mature at the encounter of the appropriate stimuli or danger signals, which induce them to perform pro-inflammatory antigen presentation to naive and memory T cells, resulting in inflammation. Remaining in an immature state however, DCs acquire a tolerogenic phenotype. When activated by TLR ligands, DCs undergo metabolic re-programming and switch to TBK1/IKKe/AKT-induced glycolysis at the early activation phase, which is sustained due to nitric oxide (NO)-mediated inhibition of mitochondrial metabolism at the later activation phase. Targeting DC activation in the view of promoting less activated or tolerogenic DCs could be an approach to reduce or abrogate inflammation in settings such as solid organ transplant rejection or in autoimmune diseases such as systemic lupus erythematosus (SLE). In this thesis, we present data pertaining to three different approaches for targeting DC activation including 1) the use of ethyl pyruvate (EP), an anti-inflammatory agent with greater efficacy than pyruvate and a putative role in metabolism alteration; 2) the use of metformin (Met), an anti-hyperglycaemic drug with a role in metabolism; 3) blocking danger signal-active HMGB1 release-from DCs with EP.

ISBN: 9781339744995Subjects--Topical Terms:

611031
Immunology.

Novel protocols to induce tolerance to solid organ transplants.
LDR:06082nmm a2200337 4500 001 2074323
005 20160926125812.5
008 170521s2016 ||||||||||||||||| ||eng d
020 $a 9781339744995
035 $a (MiAaPQ)AAI10111290
035 $a AAI10111290
040 $a MiAaPQ $c MiAaPQ
100 1 $a Chakhtoura, Marita. $3 3189625
245 1 0 $a Novel protocols to induce tolerance to solid organ transplants.
300 $a 252 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
500 $a Adviser: Stefania Gallucci.
502 $a Thesis (Ph.D.)--Temple University, 2016.
520 $a Dendritic cells (DCs) are the sentinels of the immune system. They mature at the encounter of the appropriate stimuli or danger signals, which induce them to perform pro-inflammatory antigen presentation to naive and memory T cells, resulting in inflammation. Remaining in an immature state however, DCs acquire a tolerogenic phenotype. When activated by TLR ligands, DCs undergo metabolic re-programming and switch to TBK1/IKKe/AKT-induced glycolysis at the early activation phase, which is sustained due to nitric oxide (NO)-mediated inhibition of mitochondrial metabolism at the later activation phase. Targeting DC activation in the view of promoting less activated or tolerogenic DCs could be an approach to reduce or abrogate inflammation in settings such as solid organ transplant rejection or in autoimmune diseases such as systemic lupus erythematosus (SLE). In this thesis, we present data pertaining to three different approaches for targeting DC activation including 1) the use of ethyl pyruvate (EP), an anti-inflammatory agent with greater efficacy than pyruvate and a putative role in metabolism alteration; 2) the use of metformin (Met), an anti-hyperglycaemic drug with a role in metabolism; 3) blocking danger signal-active HMGB1 release-from DCs with EP.
520 $a Ethyl pyruvate (EP), an ester derivative of pyruvate, has been shown to possess anti-inflammatory properties in various cell types in vitro and also in many animal models of disease such as severe sepsis and ischemia-reperfusion injury. EP has demonstrated greater efficacy than pyruvic acid in several experimental models and is relatively safe at clinically relevant doses. However, its effect on DCs as well as its link to the alteration of metabolism remain to be fully elucidated. In Chapter 2, we show that EP (10mM) attenuated LPS-stimulated myeloid bone marrow-derived dendritic cell (cDC) activation by reducing pro-inflammatory cytokine (IL-12, IL-6 and TNFa) and IL-10 induction, surface co-stimulatory molecule and MHC expression, the IFN-I response as well as their ability to induce T cell proliferation in vitro. Furthermore, EP could prevent LPS-induced killing normally occurring 72 hours post-stimulation. Investigating the mechanism of EP in cDCs, we found that it decreased Erk and Akt phosphorylation, thereby reducing the glycolytic rate during the early activation phase, while enhancing mitochondrial respiration and ATP production by NO blockade at the later activation phase. When administered in vivo in a murine skin transplant model, EP had very little effect on graft survival, the fact that warrants further investigation. These results indicate that EP inhibits most of the biological responses of DCs to TLR stimulation in an Erk-, Akt- and NO-dependent manner, altering the metabolic reprogramming necessary for cDC activation.
520 $a Metformin (Met) is the first-line oral treatment for type-2 diabetes mellitus but has also shown many beneficial effects encompassing lipogenesis and ovulation regulation and nephroprotection. Met activates AMPK and inhibits oxidative phosphorylation by mildly blocking the mitochondrial respiratory chain complex I. Rescuing mice from sepsis lethality and reversing lupus in SLE-prone mice, led us to explore its effects on the activation of our dendritic cells. We show that Met did not affect cytokine production or costimulation in LPS-stimulated cDCs but selectively affected MHC expression and partially inhibited NO induction. In vivo treatment of lupus-prone NZBW-F1 mice with Met and 2-DG (a glycolysis inhibitor) did not affect bone marrow cell development or the activation of cDCs differentiated in culture.
520 $a High-mobility group box-1 (HMGB1) is a nuclear non-histone DNA-binding protein, which acts as a prototypic damage-associated molecular pattern (DAMP) when in the extracellular milieu. Passively released by dead cells or actively secreted by some immunocompetent cells, HMGB1 contributes to and enhances cell maturation including that of DCs. The ability of human DCs to actively secrete HMGB1 has been established, whereas that of murine DCs remains unclear. EP has been shown to prevent HMGB1 release in many cell types, thereby decreasing inflammation. We show that our cDCs are able to actively translocate and secrete HMGB1 upon LPS stimulation, a property which is enhanced in the presence of recombinant IL-4 in the culture medium. Nevertheless, we found EP to enhance rather than inhibit HMGB1 release from our cDCs, possibly due to the attenuation of Akt phosphorylation, which could induce autophagy-mediated HMGB1 translocation.
520 $a Together, the findings in this thesis demonstrate the intricacy of the cDC activation process as well as its link to metabolism. The results also endorse the knowledge of the complex and intertwined mechanisms used in different settings by each of the agents/drugs we tested in our cDC model. The investigation of the effect of EP, Met and HMGB1 on the activation of cDCs would introduce novel protocols to promote tolerogenic DCs in the view of introducing them into the transplant or autoimmune settings. (Abstract shortened by ProQuest.).
590 $a School code: 0225.
650 4 $a Immunology. $3 611031
650 4 $a Medicine. $3 641104
650 4 $a Surgery. $3 707153
690 $a 0982
690 $a 0564
690 $a 0576
710 2 $a Temple University. $b Microbiology and Immunology. $3 3183018
773 0 $t Dissertation Abstracts International $g 77-10B(E).
790 $a 0225
791 $a Ph.D.
792 $a 2016
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10111290