Capitini Christian M, Herby Sarah, Milliron Matthew, Anver Miriam R, Mackall Crystal L, Fry Terry J
Immunology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Blood. 2009 May 14;113(20):5002-9. doi: 10.1182/blood-2008-11-187385. Epub 2009 Mar 3.
Vaccine-based expansion of T cells is one approach to enhance the graft-versus-tumor effect of allogeneic bone marrow transplantation (BMT), but the complex immunobiology of the allogeneic environment on responses to tumor vaccines has not been well characterized. We hypothesized that subclinical graft-versus-host disease (GVHD) impairs immunity, but modulation of gamma interferon (IFN-gamma) signaling could reverse this effect. Dendritic cell vaccines and donor lymphocyte infusions (DLIs) were incorporated into a minor histocompatibility antigen-mismatched, T cell-depleted, allogeneic BMT mouse model. Animals were then challenged with H-Y expressing tumors. CD4(+) and CD8(+) responses to H-Y were diminished in vaccinated allogeneic versus syngeneic BMT recipients with DLI doses below the threshold for clinical GVHD, especially in thymectomized hosts. IFN-gamma receptor 1-deficient (IFN-gammaR1(-/-)) T cells cannot cause GVHD but also have diminished vaccine responses. Remarkably, IFN-gammaR1(-/-) bone marrow abrogates GVHD, allowing higher DLI doses to be tolerated, but improves vaccine responses and tumor protection. We conclude that tumor vaccines administered after allogeneic BMT can augment graft-versus-tumor if GVHD is avoided and that prevention of IFN-gamma signaling on donor bone marrow is an effective approach to preventing GVHD while preserving immunocompetence.
基于疫苗的T细胞扩增是增强异基因骨髓移植（BMT）移植物抗肿瘤效应的一种方法，但异基因环境对肿瘤疫苗反应的复杂免疫生物学尚未得到充分表征。我们假设亚临床移植物抗宿主病（GVHD）会损害免疫功能，但调节γ干扰素（IFN-γ）信号传导可以逆转这种效应。将树突状细胞疫苗和供体淋巴细胞输注（DLI）纳入次要组织相容性抗原不匹配、T细胞去除的异基因BMT小鼠模型。然后用表达H-Y的肿瘤对动物进行攻击。在接种疫苗的异基因BMT受体与同基因BMT受体中，当DLI剂量低于临床GVHD阈值时，尤其是在胸腺切除的宿主中，对H-Y的CD4(+)和CD8(+)反应减弱。IFN-γ受体1缺陷（IFN-γR1(-/-)）的T细胞不会引起GVHD，但疫苗反应也会减弱。值得注意的是，IFN-γR1(-/-)骨髓可消除GVHD，使更高的DLI剂量能够被耐受，但可改善疫苗反应和肿瘤保护。我们得出结论，如果避免GVHD，异基因BMT后给予肿瘤疫苗可增强移植物抗肿瘤作用，并且防止供体骨髓上的IFN-γ信号传导是在保持免疫能力的同时预防GVHD的有效方法。
