Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vβ spectratype analysis in a murine bone marrow transplantation model.
Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vβ spectratype analysis in a murine bone marrow transplantation model.
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DOI：
10.4049/jimmunol.1201641
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Friedman TM
中科院分区：
文献类型：
--
作者：
Fanning SL;Zilberberg J;Stein J;Vazzana K;Berger SA;Korngold R;Friedman TM
同种异体血液和骨髓移植（BMT）作为恶性血液病的治愈性疗法的最佳使用在于成功地将具有宿主反应性并诱导移植物抗宿主病（GVHD）的成熟供体T细胞与具有肿瘤反应性并介导移植物抗白血病（GVL）效应的那些分离。为了研究这种分离在具有CBA衍生的髓性白血病细胞系MMC 6的MHC匹配的小鼠BMT模型（B10.BR→CBA）中是否可能，我们使用TCR Vβ CDR 3大小谱型分析，首先表明Vβ13家族在B10.BR抗MMC 6 CD 8 + T细胞应答中高度偏斜，但在单独针对受体细胞的同种异体应答中不偏斜。以相当于1×107个CD 8 + T细胞中的CD 8 +Vβ13+ T细胞组成的剂量（已证明在受体小鼠中介导致死性GVHD的剂量）移植CD 8 +Vβ13+ T细胞，诱导轻微GVL应答，无伴随GVHD。增加剂量的CD 8 +Vβ13+ T细胞导致更显著的GVL应答，但也增加了GVHD症状和相关死亡率。随后对GVHD靶组织的谱型分析显示肠道浸润性CD 8 +Vβ13+ T细胞参与了观察到的体内效应。当BMT受体被给予MMC 6预致敏的CD 8 +Vβ13+ T细胞时，它们显示出显著的GVL应答，具有最小的GVHD。对肿瘤致敏的肠道浸润性CD 8 +Vβ13+ T细胞的谱型分析显示，优先使用肿瘤反应性CDR 3大小的长度，并且这些细胞表达增加的效应记忆表型（CD 44 + CD 62 L-/lo）。因此，Vβ谱分析可以鉴定参与抗宿主和抗肿瘤反应性的T细胞，并且肿瘤预致敏可以帮助分离GVHD和GVL应答。
The optimum use of allogeneic blood and marrow transplantation (BMT) as a curative therapy for hematological malignancies lies in the successful separation of mature donor T cells that are host-reactive and induce graft-versus-host disease (GVHD) from those that are tumor-reactive and mediate graft-versus-leukemia (GVL) effects. To study whether this separation was possible in an MHC-matched murine BMT model (B10.BR→CBA) with a CBA-derived myeloid leukemia line, MMC6, we used TCR Vβ CDR3-size spectratype analysis to first show that the Vβ13 family was highly skewed in the B10.BR anti-MMC6 CD8+ T cell response but not in the alloresponse against recipient cells alone. Transplantation of CD8+Vβ13+ T cells at the dose equivalent of their constituency in 1×107 CD8+ T cells, a dose that had been shown to mediate lethal GVHD in recipient mice, induced a slight GVL response with no concomitant GVHD. Increasing doses of CD8+Vβ13+ T cells led to more significant GVL responses, but also increased GVHD symptoms and associated mortality. Subsequent spectratype analysis of GVHD target tissues revealed involvement of gut-infiltrating CD8+Vβ13+ T cells accounting for the observed in vivo effects. When BMT recipients were given MMC6 presensitized CD8+Vβ13+ T cells, they displayed a significant GVL response with minimal GVHD. Spectratype analysis of tumor-presensitized, gut-infiltrating CD8+Vβ13+ T cells showed preferential usage of tumor-reactive CDR3-size lengths, and these cells expressed increased effector memory phenotype (CD44+CD62L-/lo). Thus, Vβ spectratyping can identify T cells involved in anti-host and anti-tumor reactivity and tumor-presensitization can aid in the separation of GVHD and GVL responses.
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DOI：
10.1158/1078-0432.ccr-11-0503
发表时间：
2011-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Klebanoff CA;Gattinoni L;Palmer DC;Muranski P;Ji Y;Hinrichs CS;Borman ZA;Kerkar SP;Scott CD;Finkelstein SE;Rosenberg SA;Restifo NP
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Restifo NP
DOI：
10.1038/nrc3322
发表时间：
2012-10
期刊：
Nature reviews. Cancer
影响因子：
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作者：
Gattinoni L;Klebanoff CA;Restifo NP
通讯作者：
Restifo NP
DOI：
10.1073/pnas.0503726102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Klebanoff, CA;Gattinoni, L;Restifo, NP
通讯作者：
Restifo, NP
影响因子：
3.6
作者：
Higgins JP;Bernstein MB;Hodge JW
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Hodge JW
影响因子：
82.9
作者：
Figdor, CG;de Vries, IJM;Melief, CJM
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Melief, CJM