Short-Term In-Vitro Expansion Improves Monitoring and Allows Affordable Generation of Virus-Specific T-Cells against Several Viruses for a Broad Clinical Application

被引:33
作者
Geyeregger, Rene [1 ,2 ]
Freimueller, Christine [1 ,2 ]
Stevanovic, Stefan [5 ]
Stemberger, Julia [1 ,2 ]
Mester, Gabor [5 ]
Dmytrus, Jasmin [1 ,2 ]
Lion, Thomas [3 ,4 ]
Rammensee, Hans-Georg [5 ]
Fischer, Gottfried [6 ]
Eiz-Vesper, Britta [7 ]
Lawitschka, Anita [3 ,8 ]
Matthes, Susanne [3 ,8 ]
Fritsch, Gerhard [1 ,2 ,3 ]
机构
[1] St Anna Childrens Hosp, Childrens Canc Res Inst, Dept Clin Cell Biol, A-1090 Vienna, Austria
[2] St Anna Childrens Hosp, Childrens Canc Res Inst, FACS Core Unit, A-1090 Vienna, Austria
[3] Med Univ Vienna, Dept Pediat, Vienna, Austria
[4] St Anna Childrens Hosp, Childrens Canc Res Inst, Dept Mol Microbiol, A-1090 Vienna, Austria
[5] Univ Tubingen, Dept Immunol, Inst Cell Biol, Tubingen, Germany
[6] Med Univ Vienna, Dept Blood Grp Serol & Transfus Med, Vienna, Austria
[7] Hannover Med Sch, Inst Transfus Med, Hannover, Germany
[8] St Anna Childrens Hosp, Dept Stem Cell Transplantat, A-1090 Vienna, Austria
关键词
ADENOVIRUS INFECTION; ADOPTIVE TRANSFER; PERIPHERAL-BLOOD; IMMUNE RECONSTITUTION; PEDIATRIC RECIPIENTS; TRANSPLANT PATIENTS; PREEMPTIVE THERAPY; MULTIPLE VIRUSES; CYTOMEGALOVIRUS; CD8(+);
D O I
10.1371/journal.pone.0059592
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Adenoviral infections are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. Adoptive transfer of donor-derived human adenovirus (HAdV)-specific T-cells represents a promising treatment option. However, the difficulty in identifying and selecting rare HAdV-specific T-cells, and the short time span between patients at high risk for invasive infection and viremia are major limitations. We therefore developed an IL-15-driven 6 to 12 day short-term protocol for in vitro detection of HAdV-specific T cells, as revealed by known MHC class I multimers and a newly identified adenoviral CD8 T-cell epitope derived from the E1A protein for the frequent HLA-type A*02: 01 and IFN-gamma. Using this novel and improved diagnostic approach we observed a correlation between adenoviral load and reconstitution of CD8(+) and CD4(+) HAdV-specific T-cells including central memory cells in HSCT-patients. Adaption of the 12-day protocol to good manufacturing practice conditions resulted in a 2.6-log (mean) expansion of HAdV-specific T-cells displaying high cytolytic activity (4-fold) compared to controls and low or absent alloreactivity. Similar protocols successfully identified and rapidly expanded CMV-, EBV-, and BKV-specific T-cells. Our approach provides a powerful clinical-grade convertible tool for rapid and cost-effective detection and enrichment of multiple virus-specific T-cells that may facilitate broad clinical application.
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页数:15
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