Program in Immunology and Bio-Immuno-gene therapy of Cancer, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
J Immunol. 2011 Feb 1;186(3):1361-8. doi: 10.4049/jimmunol.1002030. Epub 2011 Jan 5.
Transplantation of allogeneic hematopoietic stem cells with or without immunocompetent lymphocytes has proved a successful strategy in the treatment of hematological malignancies. We have recently shown that this approach can also cure mouse prostate cancer, provided that it is combined with tumor-specific vaccination. Whether the response to alloantigens acts by providing helper function to enhance vaccine-specific responses or in other ways impinges on vaccine immunogenicity remains to be clarified, and this question is of clinical relevance. In this study, we have addressed this issue by comparing the immunogenicity of dendritic cells pulsed with a peptide derived from a tumor/viral model Ag in recipients of donor cells either syngeneic to the host or differing for either Y-encoded or multiple minor H antigens. We report that vaccination elicits comparable proliferation and differentiation of peptide-specific CD8(+) T cells despite concurrent expansion and differentiation of minor H antigen-specific IFN-γ effector T cells. Depletion of alloreactive CD4(+) T cells reduced alloreactivity but not vaccine-induced CD8(+) T cell priming, suggesting that alloresponses do not provide helper functions in peripheral lymphoid tissues. Vaccine-mediated T cell priming was also preserved in the case of multiple minor H antigen disparities, prone to graft-versus-host disease. Thus, in the context of nonmyeloablative allotransplantation aimed at restoring an effective tumor-specific T cell repertoire, minor H antigen-specific T cells do not interfere with vaccine-induced T cell priming, supporting the notion that posttransplant vaccination is a valuable strategy to boost tumor and pathogen-specific protective immunity.
同种异体造血干细胞移植联合或不联合免疫活性淋巴细胞已被证明是治疗血液系统恶性肿瘤的有效策略。我们最近表明，这种方法也可以治愈小鼠前列腺癌，只要它与肿瘤特异性疫苗接种相结合。同种异体抗原的反应是否通过提供辅助功能来增强疫苗特异性反应，或以其他方式影响疫苗免疫原性，仍有待澄清，这个问题具有临床相关性。在这项研究中，我们通过比较来自肿瘤/病毒模型 Ag 的肽脉冲处理的树突状细胞在接受供体细胞的宿主的同种异体或不同的 Y 编码或多个次要 H 抗原的受体中的免疫原性来解决这个问题。我们报告说，尽管同时扩增和分化次要 H 抗原特异性 IFN-γ效应 T 细胞，但疫苗接种会引发类似的肽特异性 CD8(+)T 细胞增殖和分化。耗竭同种反应性 CD4(+)T 细胞会降低同种反应性，但不会降低疫苗诱导的 CD8(+)T 细胞启动，这表明同种反应不会在周围淋巴组织中提供辅助功能。在易发生移植物抗宿主病的多种次要 H 抗原差异的情况下，疫苗介导的 T 细胞启动也得到了保留。因此，在旨在恢复有效肿瘤特异性 T 细胞库的非清髓性同种异体移植的背景下，次要 H 抗原特异性 T 细胞不会干扰疫苗诱导的 T 细胞启动，支持移植后疫苗接种是增强肿瘤和病原体特异性保护性免疫的有价值策略的观点。
