期刊
CURRENT OPINION IN ORGAN TRANSPLANTATION
卷 20, 期 1, 页码 13-20出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MOT.0000000000000155
关键词
chronic allograft rejection; endothelial cells; neuropilins; T cells; vascular endothelial growth factor
资金
- NIH [AI046756, AI92305, AI114223]
- Pfizer ARTS
- V. Medical Clinic, Universitatsmedizin Mannheim, Heidelberg University, Germany
- [T32DK007726]
- [T32AI007529]
Purpose of review New developments suggest that the graft itself and molecules expressed within the graft microenvironment dictate the phenotype and evolution of chronic rejection. Recent findings Once ischemia-reperfusion injury, cellular and humoral immune responses target the microvasculature, the associated local tissue hypoxia results in hypoxia-inducible factor 1 alpha-dependent expression of proinflammatory and proangiogenic growth factors including vascular endothelial growth factor (VEGF) as a physiological response to injury. Local expression of VEGF can promote the recruitment of alloimune T cells into the graft. mTOR/Akt signaling within endothelial cells regulates cytokine-and alloantibody-induced activation and proliferation and their proinflammatory phenotype. Inhibition of mTOR and/or Akt results in an anti-inflammatory phenotype and enables the expression of coinhibitory molecules that limit local T cell reactivation and promotes immunoregulation. Semaphorin family molecules may bind to neuropilin-1 on regulatory T cell subsets to stabilize functional responses. Ligation of neuropilin-1 on Tregs also inhibits Akt-induced responses suggesting common theme for enhancing local immunoregulation and long-term graft survival. Summary Events within the graft initiated by mTOR/Akt-induced signaling promote the development of chronic rejection. Semaphorin-neuropilin biology represents a novel avenue for targeting this biology and warrants further investigation.
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