Bone Marrow-Derived Mesenchymal Stromal Cells Harness Purinergenic Signaling to Tolerize Human Th1 Cells In Vivo

被引：140

作者：

Amarnath, Shoba ^{[1
]}

Foley, Jason E. ^{[1
]}

Farthing, Don E. ^{[1
]}

Gress, Ronald E. ^{[1
]}

Laurence, Arian ^{[2
]}

Eckhaus, Michael A. ^{[3
]}

Metais, Jean-Yves ^{[4
]}

Rose, Jeremy J. ^{[1
]}

Hakim, Frances T. ^{[1
]}

Felizardo, Tania C. ^{[1
]}

Cheng, Austin V. ^{[1
]}

Robey, Pamela G. ^{[5
]}

Stroncek, David E. ^{[6
]}

Sabatino, Marianna ^{[6
]}

Battiwalla, Minoo ^{[4
]}

Ito, Sawa ^{[4
]}

Fowler, Daniel H. ^{[1
]}

Barrett, Austin J. ^{[4
]}

机构：

[1] Natl Canc Inst, Cytokine Biol Sect, Expt Transplantat & Immunol Branch, Newcastle Upon Tyne, Tyne & Wear, England

[2] Newcastle Upon Tyne NHS Fdn Trust, Dept Haematol, Newcastle Upon Tyne, Tyne & Wear, England

[3] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD USA

[4] NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA

[5] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA

[6] NIH, Cell Proc Unit, Dept Transfus Med, Bethesda, MD 20892 USA

来源：

STEM CELLS | 2015年 / 33卷 / 04期

基金：

美国国家卫生研究院;

关键词：

Mesenchymal stromal cells; T cells; x-GVHD; Adenosine; REGULATORY T-CELLS; STEM-CELLS; ADENOSINE GENERATION; P2X(7) RECEPTOR; CD39; THERAPY; ACTIVATION; EXPRESSION; RESPONSES; PATHWAY;

D O I：

10.1002/stem.1934

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

The use of bone marrow-derived mesenchymal stromal cells (BMSC) in the treatment of alloimmune and autoimmune conditions has generated much interest, yet an understanding of the therapeutic mechanism remains elusive. We therefore explored immune modulation by a clinical-grade BMSC product in a model of human-into-mouse xenogeneic graft-versus-host disease (x-GVHD) mediated by human CD4(+) Th1 cells. BMSC reversed established, lethal x-GVHD through marked inhibition of Th1 cell effector function. Gene marking studies indicated BMSC engraftment was limited to the lung; furthermore, there was no increase in regulatory T cells, thereby suggesting a paracrine mechanism of BMSC action. BMSC recipients had increased serum CD73 expressing exosomes that promoted adenosine accumulation ex vivo. Importantly, immune modulation mediated by BMSC was fully abrogated by pharmacologic therapy with an adenosine A2A receptor antagonist. To investigate the potential clinical relevance of these mechanistic findings, patient serum samples collected pre- and post-BMSC treatment were studied for exosome content: CD73 expressing exosomes promoting adenosine accumulation were detected in post-BMSC samples. In conclusion, BMSC effectively modulate experimental GVHD through a paracrine mechanism that promotes adenosine-based immune suppression. Stem Cells 2015;33:1200-1212 Stem Cells2015;33:1200-1212

引用

页码：1200 / 1212

页数：13

共 45 条

[1]

Abrahamsen T G, 1991, J Clin Apher, V6, P48, DOI 10.1002/jca.2920060110

[2]

Mesenchymal-Stem-Cell-Induced Immunoregulation Involves FAS-Ligand-/FAS-Mediated T Cell Apoptosis [J].