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The Role of T-cell Costimulation in ...

Parsaud, Leon.

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The Role of T-cell Costimulation in the Pathogenesis of Kawasaki Disease.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Role of T-cell Costimulation in the Pathogenesis of Kawasaki Disease./
作者:	Parsaud, Leon.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	193 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-06, Section: B.
Contained By:	Dissertations Abstracts International81-06B.
標題:	Immunology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13856660
ISBN:	9781392536384

The Role of T-cell Costimulation in the Pathogenesis of Kawasaki Disease.
Parsaud, Leon.

The Role of T-cell Costimulation in the Pathogenesis of Kawasaki Disease. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 193 p.

Source: Dissertations Abstracts International, Volume: 81-06, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

This item must not be sold to any third party vendors.

Kawasaki disease (KD) is a multisystem vasculitis that mainly targets the coronary arteries in young children. Both environmental factors along with genetic factors play a role in the susceptibility, severity and response to treatment of KD. Regardless of the initial trigger of the immune response in KD, the role of costimulatory signals remain a critical component in the survival of T-cells and the pathogenesis of the disease. Genome wide association studies have found costimulatory molecules to be associated with KD. In this work we show that, enhanced costimulation rescued superantigen-stimulated T-cells from apoptosis. CD28 mediated signaling resulted in up-regulation of the anti-apoptotic factors, Bcl-xL and cFLIP. Bcl-xL expression was dependent on costimulatory signals and decreased with administration of CTLA-4Ig. Furthermore, expression of survival molecules cFLIP, MCL1 and NAIP were significantly upregulated in patients who did not respond to IVIG treatment. Taken together, our findings point to the important role of costimulation in the immunopathology of KD.Moreover, activation of another costimulatory molecule CD40 (via CD40L) resulted in significantly elevate lymphocyte proliferation in combination with superantigen activation. However, splenocytes from CD28 knockout mice do not exhibit this elevated response and the CD28 antagonist CTLA4-Ig was able to mimic the effects seen in the splenocytes from CD28 knockout mice. This suggests that CD28 is the intermediary that mediates the proliferative effects of CD40 activation. Furthermore, the role of platelets the largest source of sCD40L was examined. Through co-culturing experiments CD40L on activated platelets was shown to promote both splenocyte proliferation and T-cell survival upon SAg stimulation. In vivo experiments using the LCWE mouse model of KD demonstrated that coronary aneurysms are reduced in the absence of CD40L.Hence, our results indicate that costimulation mediates T-cell survival in both mice and man developing KD and regulates disease severity and treatment response, pointing to a potential new target for treatment. These studies add to our understanding of the molecular mechanisms underpinning the immunopathology of KD and identify potential biomarkers of disease and novel targets for therapy.

ISBN: 9781392536384Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

CD40

The Role of T-cell Costimulation in the Pathogenesis of Kawasaki Disease.
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520 $a Kawasaki disease (KD) is a multisystem vasculitis that mainly targets the coronary arteries in young children. Both environmental factors along with genetic factors play a role in the susceptibility, severity and response to treatment of KD. Regardless of the initial trigger of the immune response in KD, the role of costimulatory signals remain a critical component in the survival of T-cells and the pathogenesis of the disease. Genome wide association studies have found costimulatory molecules to be associated with KD. In this work we show that, enhanced costimulation rescued superantigen-stimulated T-cells from apoptosis. CD28 mediated signaling resulted in up-regulation of the anti-apoptotic factors, Bcl-xL and cFLIP. Bcl-xL expression was dependent on costimulatory signals and decreased with administration of CTLA-4Ig. Furthermore, expression of survival molecules cFLIP, MCL1 and NAIP were significantly upregulated in patients who did not respond to IVIG treatment. Taken together, our findings point to the important role of costimulation in the immunopathology of KD.Moreover, activation of another costimulatory molecule CD40 (via CD40L) resulted in significantly elevate lymphocyte proliferation in combination with superantigen activation. However, splenocytes from CD28 knockout mice do not exhibit this elevated response and the CD28 antagonist CTLA4-Ig was able to mimic the effects seen in the splenocytes from CD28 knockout mice. This suggests that CD28 is the intermediary that mediates the proliferative effects of CD40 activation. Furthermore, the role of platelets the largest source of sCD40L was examined. Through co-culturing experiments CD40L on activated platelets was shown to promote both splenocyte proliferation and T-cell survival upon SAg stimulation. In vivo experiments using the LCWE mouse model of KD demonstrated that coronary aneurysms are reduced in the absence of CD40L.Hence, our results indicate that costimulation mediates T-cell survival in both mice and man developing KD and regulates disease severity and treatment response, pointing to a potential new target for treatment. These studies add to our understanding of the molecular mechanisms underpinning the immunopathology of KD and identify potential biomarkers of disease and novel targets for therapy.
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