Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy

被引:52
作者
Bacchetta, Rosa [4 ]
Gregori, Silvia [4 ]
Serafini, Giorgia [4 ,5 ]
Sartirana, Claudia [4 ]
Schulz, Ute [6 ]
Zino, Elisabetta [4 ]
Tomiuk, Stefan [7 ]
Jansen, Uwe [7 ]
Ponzoni, Maurilio [1 ,2 ]
Paties, Carlo Terenzio [1 ,2 ]
Fleischhauer, Katharina [4 ]
Roncarolo, Maria Grazia [1 ,3 ,4 ]
机构
[1] Ist Sci San Raffaele, Pathol Unit, I-20132 Milan, Italy
[2] Ist Sci San Raffaele, Leukemia Unit, I-20132 Milan, Italy
[3] Univ Vita Salute San Raffaele, Milan, Italy
[4] San Raffaele Telethon Inst Gene Therapy HSR TIGET, Dept Regenerat Med Stem Cells & Gene Therapy, Milan, Italy
[5] Policlin Tor Vergata, Mediterranean Inst Hematol, IME Fdn, Rome, Italy
[6] Univ Regensburg, Dept Hematol & Oncol, Regensburg, Germany
[7] Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
来源
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL | 2010年 / 95卷 / 12期
关键词
regulatory T cells; immune responses; exogenous recombinant human IL-10; GROWTH-FACTOR-BETA; REGULATORY TYPE-1 CELLS; DENDRITIC CELLS; INTERLEUKIN-10; DIFFERENTIATION; IL-10; TRANSPLANTATION; TOLERANCE; RESPONSES; MARROW;
D O I
10.3324/haematol.2010.025825
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background CD4(+) regulatory T cells are a specialized subset of T cells that actively control immune responses. Several experimental protocols have been used to expand natural regulatory T cells and to generate adaptive type 1 regulatory T cells for regulatory T-cell-based therapies. Design and Methods The ability of exogenous recombinant human interleukin-10 to induce alloantigen-specific anergy in T cells was investigated and compared to that of interleukin-10 derived from tolerogenic dendritic cells, in mixed lymphocyte cultures. A detailed characterization of the effector functions of the resulting anergized T cells is reported. Results Interleukin-10, whether exogenous or derived from tolerogenic dendritic cells, induces a population of alloantigen-specific T cells (interleukin-10-anergized T cells) containing type 1 regulatory T cells, which are anergic and actively suppress alloantigen-specific effector T cells present within the mixed population. Interleukin-10-induced anergy is transforming growth factor-beta independent, and is associated with a decreased frequency of alloantigen-specific cytotoxic T lymphocyte precursors, but interleukin-10-anergized T cells are still responsive to third-party, bacterial, and viral antigens. Tolerogenic dendritic cells are more powerful than exogenous interleukin-10 in generating type 1 regulatory T-cell precursors, and are also effective in the context of HLA-matched donors. Conclusions Based on these studies, we have developed an efficient and reproducible in vitro method to generate antigen-specific type 1 regulatory T-cell precursors starting from total peripheral blood cells with minimal cell manipulation and suitable for generating type 1 regulatory T cells for regulatory T-cell-based therapies.
引用
收藏
页码:2134 / 2143
页数:10
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