Hasan Aisha N, Kollen Wouter J, Trivedi Deepa, Selvakumar Annamalai, Dupont Bo, Sadelain Michel, O'Reilly Richard J
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Immunol. 2009 Aug 15;183(4):2837-50. doi: 10.4049/jimmunol.0804178. Epub 2009 Jul 27.
Adoptive transfer of virus-specific T cells can treat infections complicating allogeneic hematopoietic cell transplants. However, autologous APCs are often limited in supply. In this study, we describe a panel of artificial APCs (AAPCs) consisting of murine 3T3 cells transduced to express human B7.1, ICAM-1, and LFA-3 that each stably express one of a series of six common HLA class I alleles. In comparative analyses, T cells sensitized with AAPCs expressing a shared HLA allele or autologous APCs loaded with a pool of 15-mer spanning the sequence of CMVpp65 produced similar yields of HLA-restricted CMVpp65-specific T cells; significantly higher yields could be achieved by sensitization with AAPCs transduced to express the CMVpp65 protein. T cells generated were CD8(+), IFN-gamma(+), and exhibited HLA-restricted CMVpp65-specific cytotoxicity. T cells sensitized with either peptide-loaded or transduced AAPCs recognized epitopes presented by each HLA allele known to be immunogenic in humans. Sensitization with AAPCs also permitted expansion of IFN-gamma(+) cytotoxic effector cells against subdominant epitopes that were either absent or in low frequencies in T cells sensitized with autologous APCs. This replenishable panel of AAPCs can be used for immediate sensitization and expansion of virus-specific T cells of desired HLA restriction for adoptive immunotherapy. It may be of particular value for recipients of transplants from HLA-disparate donors.
病毒特异性T细胞的过继转移可治疗异基因造血细胞移植相关的感染。然而，自体抗原呈递细胞（APC）的供应往往有限。在本研究中，我们描述了一组人工APC（AAPC），其由转导表达人B7.1、细胞间黏附分子-1（ICAM-1）和淋巴细胞功能相关抗原-3（LFA-3）的小鼠3T3细胞组成，这些细胞各自稳定表达一系列六个常见HLA I类等位基因中的一个。在比较分析中，用表达共享HLA等位基因的AAPC致敏的T细胞或负载覆盖巨细胞病毒（CMV）pp65序列的15聚体库的自体APC产生的HLA限制性CMV pp65特异性T细胞产量相似；通过用转导表达CMV pp65蛋白的AAPC致敏可实现显著更高的产量。产生的T细胞为CD8(+)、γ干扰素（IFN-γ）(+)，并表现出HLA限制性CMV pp65特异性细胞毒性。用负载肽或转导的AAPC致敏的T细胞识别已知在人类中具有免疫原性的每个HLA等位基因呈递的表位。用AAPC致敏还允许针对在用自体APC致敏的T细胞中不存在或频率较低的亚显性表位扩增IFN-γ(+)细胞毒性效应细胞。这组可补充的AAPC可用于立即致敏和扩增用于过继免疫治疗的具有所需HLA限制性的病毒特异性T细胞。对于来自HLA不相合供体的移植受者可能具有特别价值。
