Schub Andrea, Schuster Ingrid G, Hammerschmidt Wolfgang, Moosmann Andreas
Department of Gene Vectors, Helmholtz Zentrum München, Munich, Germany.
J Immunol. 2009 Nov 15;183(10):6819-30. doi: 10.4049/jimmunol.0902233. Epub 2009 Oct 28.
Reactivation of CMV can cause severe disease after allogeneic hemopoietic stem cell transplantation. Adoptive T cell therapy was successfully used for patients who had received transplants from CMV-positive donors. However, patients with transplants from CMV-negative donors are at highest risk, and an adoptive therapy is missing because CMV-specific T cells are not available from such donors. To address this problem, we used retroviral transfer of CMV-specific TCR genes. We generated CMV-specific T cell clones of several HLA restrictions recognizing the endogenously processed Ag pp65. The genes of four TCRs were cloned and transferred to primary T cells from CMV-negative donors. These CMV-TCR-transgenic T cells displayed a broad spectrum of important effector functions (secretion of IFN-gamma and IL-2, cytotoxicity, proliferation) in response to endogenously processed pp65 and could be enriched and expanded by strictly Ag-specific stimulation. Expansion of engineered T cells was accompanied by an increase in specific effector functions, indicating that the transferred specificity is stable and fully functional. Hence, we expect these CMV-TCR-transgenic T cells to be effective in controlling acute CMV disease and establishing an antiviral memory.
巨细胞病毒（CMV）再激活可在异基因造血干细胞移植后引发严重疾病。过继性T细胞疗法已成功应用于接受来自CMV阳性供体移植的患者。然而，接受来自CMV阴性供体移植的患者风险最高，且由于无法从此类供体获得CMV特异性T细胞，因而缺少过继性疗法。为解决这一问题，我们采用了逆转录病毒介导的CMV特异性TCR基因转移。我们生成了多个识别内源性加工抗原pp65的不同HLA限制型的CMV特异性T细胞克隆。克隆了四个TCR的基因并将其转移至来自CMV阴性供体的原代T细胞。这些CMV-TCR转基因T细胞在对内源性加工的pp65作出反应时表现出广泛的重要效应功能（分泌IFN-γ和IL-2、细胞毒性、增殖），并且可通过严格的抗原特异性刺激进行富集和扩增。工程化T细胞的扩增伴随着特异性效应功能的增强，表明转移的特异性稳定且功能完全。因此，我们期望这些CMV-TCR转基因T细胞在控制急性CMV疾病和建立抗病毒记忆方面有效。
