Graft-versus-leukemia (GVL) against mouse blast-crisis chronic myelogenous leukemia (BC-CML) and chronic-phase chronic myelogenous leukemia (CP-CML): shared mechanisms of T cell killing, but programmed death ligands render CP-CML and not BC-CML GVL resistant.
Graft-versus-leukemia (GVL) against mouse blast-crisis chronic myelogenous leukemia (BC-CML) and chronic-phase chronic myelogenous leukemia (CP-CML): shared mechanisms of T cell killing, but programmed death ligands render CP-CML and not BC-CML GVL resistant.
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DOI：
10.4049/jimmunol.1100311
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发表时间：
2011-08-15
期刊：
影响因子：
--
通讯作者：
Shlomchik WD
中科院分区：
文献类型：
--
作者：
Matte-Martone C;Venkatesan S;Tan HS;Athanasiadis I;Chang J;Pavisic J;Shlomchik WD
GVL对慢性期CML（CP-CML）有效，但对急性白血病和急变期CML（BC-CML）效果较差。GVL抗性的潜在机制尚不清楚。以前，我们发现同种异体反应性T细胞靶向GVL敏感的bcr-abl诱导的小鼠CP-CML（mCP-CML）需要TCR：MHC相互作用，并且多种和冗余的杀伤机制在起作用。为了更好地理解BC-CML对GVL耐药的原因，我们对由逆转录病毒转移bcr-abl和NUP 98/HOXA 9融合cDNA诱导的针对小鼠BC-CML（mBC-CML）的GVL进行了全面分析。与人BC-CML一样，mBC-CML是GVL耐药的，这不是由于加速的动力学或更大的白血病负荷。为了研究T细胞识别和杀伤机制，我们通过转导基因缺陷小鼠的骨髓产生了一组基因缺陷型白血病。mBC-CML细胞表达抗mCP-CML的MHC和GVL是T细胞靶向识别的绝对必要条件，mBC-CML需要白血病细胞表达ICAM-1。我们假设mBC-CML对一些足以消除mCP-CML的杀伤机制具有抗性，但我们发现，相同的机制对两种类型的白血病都有效，因为GVL对野生型或mBC-CML基因缺乏Fas，TRAIL-R，Fas/TRAIL-R，TNFR 1/R2或供体T细胞是穿孔素−/−时相似。然而，mCP-CML而不是mBC-CML依赖于PD配体的表达来抵抗T细胞杀伤，因为当白血病缺乏PD-L1/L2时，仅针对mCP-CML的GVL增强。因此，mBC-CML细胞具有与mCP-CML细胞不同的细胞内在机制，保护它们免受T细胞杀伤。
GVL against chronic phase CML (CP-CML) is potent, but it is less efficacious against acute leukemias and blast crisis CML (BC-CML). The mechanisms underlying GVL-resistance are unknown. Previously, we found that alloreactive T cell targeting of GVL-sensitive bcr-abl-induced mouse CP-CML (mCP-CML) required TCR:MHC interactions and that multiple and redundant killing mechanisms were in play. To better understand why BC-CML is resistant to GVL, we performed a comprehensive analysis of GVL against mouse BC-CML (mBC-CML) induced by the retroviral transfer of the bcr-abl and NUP98/HOXA9 fusion cDNAs. Like human BC-CML, mBC-CML was GVL-resistant, and this was not due to accelerated kinetics or a greater leukemia burden. To study T cell recognition and killing mechanisms, we generated a panel of gene-deficient leukemias by transducing bone marrow from gene-deficient mice. T cell target recognition absolutely required that mBC-CML cells express MHC and GVL against both mCP-CML and mBC-CML required leukemia expression of ICAM-1. We hypothesized that mBC-CML would be resistant to some of the killing mechanisms sufficient to eliminate mCP-CML, but we found instead that the same mechanisms were effective against both types of leukemia as GVL was similar against wild type or mBC-CML genetically lacking Fas, TRAIL-R, Fas/TRAIL-R, TNFR1/R2 or when donor T cells were perforin−/−. However, mCP-CML but not mBC-CML, relied on expression of PD-ligands to resist T cell killing, as only GVL against mCP-CML was augmented when leukemias lacked PD-L1/L2. Thus, mBC-CML cells have cell-intrinsic mechanisms distinct from mCP-CML cells that protect them from T cell killing.
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DOI：
10.1084/jem.188.12.2357
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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DOI：
10.1073/pnas.102583199
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2002-05-28
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