Graft-versus-host disease impairs vaccine responses through decreased CD4+ and CD8+ T cell proliferation and increased perforin-mediated CD8+ T cell apoptosis.
Graft-versus-host disease impairs vaccine responses through decreased CD4+ and CD8+ T cell proliferation and increased perforin-mediated CD8+ T cell apoptosis.
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DOI：
10.4049/jimmunol.1200391
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发表时间：
2013-02-01
期刊：
影响因子：
--
通讯作者：
Fry TJ
中科院分区：
文献类型：
--
作者：
Capitini CM;Nasholm NM;Duncan BB;Guimond M;Fry TJ
肿瘤靶向疫苗代表了增强异基因血液或骨髓移植（alloBMT）后移植物抗白血病效应的策略。我们以前已经表明，GVHD可以对疫苗的定量反应产生负面影响。我们使用次要组织相容性抗原（mHA）错配的BMT（B6 → B6 × C3H.SW），然后过继转移HY特异性T细胞和表达HY的树突状细胞，评估供体淋巴细胞输注（DLI）诱导的GVHD是否影响疫苗应答的非同种抗原反应性T细胞的持续性、增殖和存活。CD 8+和CD 4 + HY特异性T细胞在具有GVHD的同种异体受体中经历较少的疫苗驱动的增殖。虽然疫苗应答性CD 8 + T细胞显示γ干扰素和CD 107 a产生减少，但CD 4 + T细胞表现出PD-1和TIM 3表达增加。此外，在存在GVHD的情况下，疫苗应答的CD 8 + T细胞的凋亡程度更高，但CD 4 + T细胞凋亡没有差异。使用Fas配体缺陷或TRAIL缺陷的DLI对HY特异性T细胞的凋亡没有影响。然而，穿孔素缺陷的同种异体反应性DLI诱导的疫苗应答性CD 8 + T细胞凋亡显著减少，并导致增强的肿瘤保护。因此，GVHD期间疫苗应答减弱是由于响应于疫苗接种的CD 8+和CD 4 + T细胞增殖受损，以及穿孔素介导的CD 8 + T细胞凋亡的额外贡献。这些结果为优化alloBMT后的疫苗应答提供了重要的见解。
Tumor-targeted vaccines represent a strategy to enhance the graft-versus-leukemia effect following allogeneic blood or marrow transplantation (alloBMT). We have previously shown that GVHD can negatively impact quantitative responses to vaccines. Using a minor histocompatibility antigen (mHA)-mismatched BMT (B6 → B6 × C3H.SW) followed by adoptive transfer of HY-specific T cells and HY-expressing dendritic cells we assessed whether GVHD induced by donor lymphocyte infusion (DLI) affects the persistence, proliferation and survival of vaccine-responding, nonalloantigen reactive T cells. Both CD8+ and CD4+ HY-specific T cells undergo less vaccine-driven proliferation in allogeneic recipients with GVHD. While vaccine responding CD8+ T cells show decreased gamma interferon and CD107a production, CD4+ T cells exhibit increased PD-1 and TIM3 expression. In addition, the degree of apoptosis in vaccine-responding CD8+ T cells was higher in the presence of GVHD, but there was no difference in CD4+ T cell apoptosis. Using Fas ligand-deficient or TRAIL-deficient DLI had no impact on apoptosis of HY-specific T cells. However, perforin-deficient alloreactive DLI induced significantly less apoptosis of vaccine-responding CD8+ T cells, and resulted in enhanced tumor protection. Thus, diminished vaccine responses during GVHD result from impaired proliferation of CD8+ and CD4+ T cells responding to vaccination, with an additional contribution from perforin-mediated CD8+ T cell apoptosis. These results provide important insights towards optimizing vaccine responses after alloBMT.
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DOI：
10.1084/jem.183.6.2645
发表时间：
1996-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Baker MB;Altman NH;Podack ER;Levy RB
通讯作者：
Levy RB
DOI：
10.1158/1078-0432.ccr-08-3332
发表时间：
2009-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Beatty GL;Smith JS;Reshef R;Patel KP;Colligon TA;Vance BA;Frey NV;Johnson FB;Porter DL;Vonderheide RH
通讯作者：
Vonderheide RH
影响因子：
30.5
作者：
Lantz, O;Grandjean, I;Di Santo, JP
通讯作者：
Di Santo, JP
影响因子：
32.4
作者：
Grossman, WJ;Verbsky, JW;Ley, TJ
通讯作者：
Ley, TJ
影响因子：
20.3
作者：
Jenq, Robert R.;King, Christopher G.;van den Brink, Marcel R. M.
通讯作者：
van den Brink, Marcel R. M.