Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells

被引：126

作者：

Hippen, Keli L. ^{[1
,2
]}

Harker-Murray, Paul ^{[1
,2
]}

Porter, Stephen B. ^{[1
,2
]}

Merkel, Sarah C. ^{[1
,2
]}

Londer, Aryel ^{[1
,2
]}

Taylor, Dawn K. ^{[1
,2
]}

Bina, Megan ^{[1
,2
]}

Panoskaltsis-Mortari, Angela ^{[1
,2
]}

Rubinstein, Pablo ^{[3
]}

Van Rooijen, Nico ^{[4
]}

Golovina, Tatiana N. ^{[5
]}

Suhoski, Megan M. ^{[5
]}

Miller, Jeffrey S. ^{[1
,6
]}

Wagner, John E. ^{[1
,2
]}

June, Carl H. ^{[5
]}

Riley, James L. ^{[5
]}

Blazar, Bruce R. ^{[1
,2
]}

机构：

[1] Univ Minnesota, Ctr Canc, Div Bone Blood & Marrow Transplantat, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Dept Pediat, Div Bone Blood & Marrow Transplantat, Minneapolis, MN 55455 USA

[3] New York Blood Ctr, Natl Cord Blood Program, New York, NY 10021 USA

[4] Vrije Univ Amsterdam, Dept Mol & Cell Biol, Amsterdam, Netherlands

[5] Univ Penn, Ctr Canc, Abramson Family Canc Ctr, Res Inst, Philadelphia, PA 19104 USA

[6] Univ Minnesota, Dept Med, Div Bone Blood & Marrow Transplantat, Minneapolis, MN 55455 USA

来源：

BLOOD | 2008年 / 112卷 / 07期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1182/blood-2008-01-132951

中图分类号：

R5 [内科学];

学科分类号：

1002 [临床医学]; 100201 [内科学];

摘要：

Previously, we showed that human umbilical cord blood (UCB) regulatory T cells (Tregs) could be expanded approximately 100-fold using anti-CD3/28 monoclonal antibody (mAb)-coated beads to provide T-cell receptor and costimulatory signals. Because Treg numbers from a single UCB unit are limited, we explored the use of cell-based artificial antigen-presenting cells (aAPCs) preloaded with anti-CD3/28 mAbs to achieve higher levels of Treg expansion. Compared with beads, aAPCs had similar expansion properties while significantly increasing transforming growth factor beta (TGF-beta) secretion and the potency of Treg suppressor function. aAPCs modified to coexpress OX40L or 4-1BBL expanded UCB Tregs to a significantly greater extent than bead- or non-modified aAPC cultures, reaching mean expansion levels exceeding 1250-fold. Despite the high expansion and in contrast to studies using other Treg sources, neither OX40 nor 4-1BB signaling of UCB Tregs reduced in vitro suppression. UCB Tregs expanded with 4-1BBL expressing aAPCs had decreased levels of proapoptotic bim. UCB Tregs expanded with non-modified or modified aAPCs versus beads resulted in higher survival associated with increased Treg persistence in a xenogeneic graft-versus-host disease lethality model. These data offer a novel approach for UCB Treg expansion using aAPCs, including those coexpressing OX40L or 4-1BBL.

引用

页码：2847 / 2857

页数：11

共 55 条

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