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The Impact of Obesity on Graft-Versu...

Khuat, Lam Tan.

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The Impact of Obesity on Graft-Versus-Host Disease Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Impact of Obesity on Graft-Versus-Host Disease Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation./
Author:	Khuat, Lam Tan.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	107 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
Subject:	Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10982378
ISBN:	9780438930858

The Impact of Obesity on Graft-Versus-Host Disease Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation.
Khuat, Lam Tan.

The Impact of Obesity on Graft-Versus-Host Disease Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 107 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--University of California, Davis, 2018.

This item must not be added to any third party search indexes.

Hematopoietic stem cell transplantation (HSCT) is being widely used to treat a variety of hematological malignancies. However, graft-versus-host disease (GVHD) generated by donor T cell attack on the host tissues is still the main limitation for clinical application of HSCT to patients. This dissertation aims to summarize the current knowledge on GVHD mechanisms, as well as provide novel information on chronic GVHD treatment in mice using proteasome inhibitor pevonedistat, and more importantly, evaluate the impact of obesity on GVHD outcomes in the recipients post-HSCT in mice and human patients. Here we show that targeting proteasome with pevonedistat successfully mitigates sclerodermatous GVHD while maintaining the graft-versus-tumor (GVT) effects in a minor histocompatibility antigen mismatch HSCT setting, a well-established skin GVHD model. Interestingly, by using the same model but using low-fat diet and high-fat diet-fed mice as the recipients, we observe a paradigm shift in GVHD outcomes in which obesity results in lethal acute GVHD targeting the gastrointestinal tract. A clinical study led by our collaborators also demonstrates that obese patients have a significant decreased survival rate compared to non-obese patients post allogeneic HSCT. Administration of pro-inflammatory cytokine signaling inhibitors or antibiotics prophylactically ameliorates the acute GVHD in obese mice. Taken together, this is the first study to address the negative correlation between obesity and GVHD outcomes in mice and human and suggest some promising therapies to reduce the mortality of acute GVHD in the obese recipients.

ISBN: 9780438930858Subjects--Topical Terms:

518431
Physiology.

The Impact of Obesity on Graft-Versus-Host Disease Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation.
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520 $a Hematopoietic stem cell transplantation (HSCT) is being widely used to treat a variety of hematological malignancies. However, graft-versus-host disease (GVHD) generated by donor T cell attack on the host tissues is still the main limitation for clinical application of HSCT to patients. This dissertation aims to summarize the current knowledge on GVHD mechanisms, as well as provide novel information on chronic GVHD treatment in mice using proteasome inhibitor pevonedistat, and more importantly, evaluate the impact of obesity on GVHD outcomes in the recipients post-HSCT in mice and human patients. Here we show that targeting proteasome with pevonedistat successfully mitigates sclerodermatous GVHD while maintaining the graft-versus-tumor (GVT) effects in a minor histocompatibility antigen mismatch HSCT setting, a well-established skin GVHD model. Interestingly, by using the same model but using low-fat diet and high-fat diet-fed mice as the recipients, we observe a paradigm shift in GVHD outcomes in which obesity results in lethal acute GVHD targeting the gastrointestinal tract. A clinical study led by our collaborators also demonstrates that obese patients have a significant decreased survival rate compared to non-obese patients post allogeneic HSCT. Administration of pro-inflammatory cytokine signaling inhibitors or antibiotics prophylactically ameliorates the acute GVHD in obese mice. Taken together, this is the first study to address the negative correlation between obesity and GVHD outcomes in mice and human and suggest some promising therapies to reduce the mortality of acute GVHD in the obese recipients.
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