Ex vivo generation of regulatory T cells from liver transplant recipients using costimulation blockade

被引:7
|
作者
Shimozawa, Katsuyoshi [1 ,2 ]
Contreras-Ruiz, Laura [1 ]
Sousa, Sofia [1 ]
Zhang, Ruan [1 ]
Bhatia, Urvashi [1 ]
Crisalli, Kerry C. [3 ,4 ]
Brennan, Lisa L. [1 ]
Turka, Laurence A. [3 ,4 ]
Markmann, James F. [3 ,4 ,5 ]
Guinan, Eva C. [1 ,6 ]
机构
[1] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA
[2] Nihon Univ, Sch Med, Dept Pediat & Child Hlth, Tokyo, Japan
[3] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA
[4] Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02114 USA
[5] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA
[6] Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
costimulation; hepatology; immune modulation; immunosuppressant; fusion proteins and monoclonal antibodies; belatacept; immunosuppression; liver transplantation; T cell biology; tolerance; translational research; DE-NOVO MALIGNANCIES; KIDNEY-TRANSPLANTATION; IMMUNE DYSFUNCTION; METABOLIC SYNDROME; GENE-EXPRESSION; RISK-FACTORS; END-STAGE; TOLERANCE; THERAPY; IMMUNOSUPPRESSION;
D O I
10.1111/ajt.16842
中图分类号
R61 [外科手术学];
学科分类号
摘要
The potential of adoptive cell therapy with regulatory T cells (Tregs) to promote transplant tolerance is under active exploration. However, the impact of specific transplant settings and protocols on Treg manufacturing is not well-delineated. Here, we compared the use of peripheral blood mononuclear cells (PBMCs) from patients before or after liver transplantation to the use of healthy control PBMCs to determine their suitability for Treg manufacture using ex vivo costimulatory blockade with belatacept. Despite liver failure or immunosuppressive therapy, the capacity for Treg expansion during the manufacturing process was preserved. These experiments did not identify performance or quality issues that disqualified the use of posttransplant PBMCs-the currently favored protocol design. However, as Treg input correlated with output, significant CD4-lymphopenia in both pre- and posttransplant patients limited Treg yield. We therefore turned to leukapheresis posttransplant to improve absolute yield. To make deceased donor use feasible, we also developed protocols to substitute splenocytes for PBMCs as allostimulators. In addition to demonstrating that this Treg expansion strategy works in a liver transplant context, this preclinical study illustrates how characterizing cellular input populations and their performance can both inform and respond to clinical trial design and Treg manufacturing requirements.
引用
收藏
页码:504 / 518
页数:15
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