Oncotarget

Research Papers:

Obese donor mice splenocytes aggravated the pathogenesis of acute graft-versus-host disease via regulating differentiation of Tregs and CD4+ T cell induced-type I inflammation

Zengyao Li, Jian Gu, Qin Zhu, Jing Liu, Hao Lu, Yunjie Lu and Xuehao Wang _

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Oncotarget. 2017; 8:74880-74896. https://doi.org/10.18632/oncotarget.20425

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Abstract

Zengyao Li1,*, Jian Gu1,*, Qin Zhu1,*, Jing Liu2, Hao Lu1, Yunjie Lu1 and Xuehao Wang1

1Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China

2Department of Radiotherapy, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China

*These authors have contributed equally to this work

Correspondence to:

Xuehao Wang, email: wangxh@njmu.edu.cn

Keywords: obesity, aGVHD, transplantation

Received: April 21, 2017    Accepted: June 04, 2017    Published: August 24, 2017

ABSTRACT

Acute graft-versus-host disease (aGVHD) remains one of the most severe complications in organ and bone marrow transplantation, leading to much morbidity and mortality. Obesity has been associated with increased risk of development of various inflammatory diseases. Here, we investigated the in vitro and in vivo effects of obese donor splenocytes on the development of acute graft-versus-host disease (aGVHD). In this study, mixed lymphocyte reactions (MLR) in vitro showed that obese donor mouse CD4+ T cell promoted the production of interleukin-2 (IL-2), interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Meanwhile, the inducible Tregs population decreased greatly in obese donor mouse CD4+ T cells’ induction group, compared with normal group. Then in the murine aGVHD model, we found that obese donor splenocytes dramatically increased the severity of aGVHD through down-regulating immune tolerance while enhancing systemic and local immunity. Moreover, we showed that aGVHD induced by obese donors resulted in massive expansion of donor CD3+ T cells, release of Th1-related cytokines, interleukin-17 (IL-17) and chemokines, significant increase of Th17 cells and inhibition of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and impaired suppressive ability of donor Tregs. Expression of sphingosine-1-phosphate receptor 1 (S1PR1), phosphorylated Akt, mammalian target of rapamycin (mTOR) and Raptor increased, while the phosphorylation level of SMAD3 was decreased in the skin, intestine, lung and liver from obese donor splenocytes-treated aGVHD mice. Furthermore, at mRNA and protein levels, we defined several molecules that may account for the enhanced ability of obese donor splenocytes to migrate into target organs, such as IL-2, IL-17, IFN-γ, TNF-α, CXCR3, CXCL9, CXCL10, CXCL11 and CCL3. Therefore, these results imply that obese donor cells may be related to the risk of aGVHD and helping obese donor individuals lose weight represent a compulsory clinical strategy before implementing transplantation to control aGVHD of recipients.


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