Limitations of CD95 ligand‐transduced killer dendritic cells to prevent graft rejections
Limitations of CD95 ligand‐transduced killer dendritic cells to prevent graft rejections
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DOI：
10.1111/j.0906-6705.2005.00307.x
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发表时间：
2005-04
影响因子：
3.6
通讯作者：
M. Kusuhara;H. Matsue
中科院分区：
文献类型：
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作者：
M. Kusuhara;H. Matsue
摘要：作为实验诱导抗原（Ag）特异性免疫抑制的尝试，我们先前已经创建了CD 95配体（CD 95 L）转导的树突状细胞（DC），其在体外以Ag依赖性方式向CD 4 + T细胞递送凋亡信号，但不活化信号。我们还证明，将CD 95 L转导的DC（称为杀伤DC）注射到同基因动物中可抑制对所施用Ag的迟发型超敏反应。基于这些发现，我们测试了将源自A/J小鼠（H-2a）的杀伤DC注射到同种异体BALB/c受体（H-2d）中是否可以通过耗尽A/J反应性效应T细胞来延长A/J衍生皮肤移植物的存活。这一尝试没有成功。在这项研究中，我们阐明了这种失败的原因，特别是在体外效应的杀伤DC在体内引发同种异体反应性T细胞。我们发现，杀伤DC（i）不能以CD 95/CD 95 L依赖的方式诱导幼稚同种异体反应性T细胞的增殖，（ii）抑制体内引发的同种异体反应性T细胞的增殖，（iii）杀死相对小的分数（高达30%）的这些T细胞在体外以CD 95/CD 95 L依赖的方式和（iv）显着，但不完全，抑制产生针对A/J决定簇的细胞毒性T淋巴细胞活性。因此，杀伤DC具有显著但适度的抑制体外同种异体免疫应答的能力，这可能不足以延长严格同种异体移植模型中同种异体皮肤移植物的存活。这项研究表明，目前的杀手DC技术的形式需要更多的修改，其临床应用，以防止移植排斥反应。
Abstract: As an attempt to experimentally induce antigen (Ag)‐specific immunosuppression, we have previously created CD95 ligand (CD95L)‐transduced dendritic cells (DC), which delivered apoptotic, but not activation, signals to CD4+ T cells in vitro in an Ag‐dependent manner. We have also demonstrated that CD95L‐transduced DC (termed killer DC) injected into syngeneic animals suppressed delayed‐type hypersensitivity responses to an administered Ag. Based on these findings, we tested whether the injection of killer DC derived from A/J mice (H‐2a) into allogeneic BALB/c recipients (H‐2d) could prolong the survival of A/J‐derived skin grafts by depleting A/J‐reactive effector T cells. This attempt has not been successful. In this study, we elucidate the reasons for this failure, especially in terms of in vitro effects of killer DC on in vivo primed alloreactive T cells. We show that killer DC (i) failed to induce the proliferation of naive alloreactive T cells in a CD95/CD95L‐dependent fashion, (ii) inhibited the proliferation of in vivo primed alloreactive T cells, (iii) killed relatively small fractions (up to 30%) of these T cells in vitro in a CD95/CD95L‐dependent fashion and (iv) significantly, but incompletely, inhibited the generation of cytotoxic T‐lymphocyte activities against A/J determinants. Thus, killer DC have significant, but modest, capacities to suppress in vitro alloimmune responses, which may not be sufficient to prolong the survival of alloskin grafts in a stringent allograft model. This study suggests that the current format of killer DC technology requires more modifications for its clinical application to prevent graft rejection.