Hanley Patrick J, Melenhorst Jan J, Nikiforow Sarah, Scheinberg Phillip, Blaney James W, Demmler-Harrison Gail, Cruz C Russell, Lam Sharon, Krance Robert A, Leung Kathryn S, Martinez Caridad A, Liu Hao, Douek Daniel C, Heslop Helen E, Rooney Cliona M, Shpall Elizabeth J, Barrett A John, Rodgers John R, Bollard Catherine M
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA.
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Transl Med. 2015 Apr 29;7(285):285ra63. doi: 10.1126/scitranslmed.aaa2546.
Adoptive transfer of cytomegalovirus (CMV)-specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naïve cells for T cell therapy. Naïve T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV-seropositive individuals; however, these two cell populations had similar avidities. CMV-seropositive individuals also had T cells recognizing these atypical epitopes, but these cells had a lower avidity than those derived from the seronegative subjects, which suggests that high-avidity T cells to these epitopes may be lost over time. Indeed, recipients of cord blood (CB) grafts who did not develop CMV were found by clonotypic analysis to have T cells recognizing atypical CMVpp65 epitopes. Therefore, we examined unmanipulated CB units and found that T cells with T cell receptors restricted by atypical epitopes were the most common, which may explain why these T cells expanded. When infused to recipients, naïve donor-derived virus-specific T cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. These data suggest that naïve-derived T cells from seronegative patients may be an additional source of cells for CMV immunoprophylaxis.
移植来自成年血清反应阳性供体的巨细胞病毒（CMV）特异性T细胞可有效恢复移植后的抗病毒免疫力。然而，CMV血清反应阴性的供体缺乏CMV特异性记忆T细胞，这限制了用于免疫预防的病毒特异性T细胞的可及性。我们证明了从幼稚细胞中获得CMV特异性T细胞用于T细胞治疗的可行性。经致敏以识别CMV的幼稚T细胞识别的是与来自CMV血清反应阳性个体的T细胞不同的、非典型表位；然而，这两种细胞群体具有相似的亲和力。CMV血清反应阳性个体也有识别这些非典型表位的T细胞，但这些细胞的亲和力低于血清反应阴性个体来源的T细胞，这表明随着时间推移，针对这些表位的高亲和力T细胞可能会丢失。事实上，通过克隆型分析发现，未发生CMV感染的脐血（CB）移植受者有识别非典型CMVpp65表位的T细胞。因此，我们检查了未处理的CB单位，发现受非典型表位限制的T细胞受体的T细胞最为常见，这可能解释了为什么这些T细胞会扩增。当输注给受者时，识别非典型表位的幼稚供体来源的病毒特异性T细胞与延长的无CMV生存期和完全缓解相关。这些数据表明，血清反应阴性患者来源的幼稚T细胞可能是CMV免疫预防的另一种细胞来源。
