In vivo elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer
In vivo elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer
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DOI：
10.1111/j.0906-6705.2004.00198.x
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发表时间：
2004-10-01
影响因子：
3.6
通讯作者：
Ichihashi, M
中科院分区：
文献类型：
--
作者：
Nagai, H;Horikawa, T;Ichihashi, M
CD4(+)CD25(+) T细胞是一个重要的群体，在维持外周自身耐受中起着至关重要的作用。最近，研究表明，体内给药抗cd25单克隆抗体（mAb）消除这些细胞可导致同基因小鼠高免疫原性肿瘤的消退。在这项研究中，我们检测了B16F10黑色素瘤细胞是否随着CD25（+）调节性T细胞的消除而退化。我们发现黑色素瘤细胞完全不受体内抗cd25单抗单独给药的影响，但当给药与IL-12基因转移到肿瘤细胞时，所有小鼠都产生了肿瘤排斥反应。在体内，自然杀伤（NK）细胞或CD8(+) T细胞的消耗消除了肿瘤的排斥反应。nk细胞耗损使得IL-12转染的B16F10黑色素瘤（B16/IL-12）从早期阶段开始生长，并且导致B16/IL-12的肿瘤生长速度比未给予抗cd25单抗的小鼠更快。另一方面，CD8(+) t细胞耗尽不影响肿瘤早期的生长，但允许B16/IL-12在相当晚的阶段生长，并且导致与未施用抗cd25单抗的小鼠几乎相同的肿瘤生长程度。在之前的研究中，我们发现消除CD4(+) T细胞可增强B16/IL-12的抗肿瘤作用，并诱导白癜风样毛色改变。因此，我们还研究了CD25(+) t细胞消除引起肿瘤排斥的小鼠白癜风样毛色变化的频率，以比较细胞消除增强抗肿瘤作用的机制。CD25(+) T细胞的消除不会引起白癜风样的毛色变化，尽管CD4(+) T细胞在60%的小鼠中引起了这种变化。此外，我们证实，消除CD25(+) T细胞不影响辅助性T细胞（Th） 1/Th2细胞因子谱，而CD4(+)T细胞消除Th2细胞因子（IL-4和IL-10）并导致B16/ il -12小鼠肿瘤引流淋巴结（tdln）中th1显性细胞因子谱。这些结果表明，体内CD25（+）调节性T细胞的缺失与IL-12基因转移相结合，在B16F10黑色素瘤的免疫治疗中是一种有效的辅助剂，CD25(+) T细胞缺失增强抗肿瘤效果是通过CD8(+) T细胞介导的，可能不同于CD4(+) T细胞缺失引起的增强机制。
CD4(+)CD25(+) T cells are an important population that plays a crucial role in the maintenance of peripheral self-tolerance. Recently, it was shown that the elimination of these cells by in vivo administration of anti-CD25 monoclonal antibody (mAb) caused the regression of highly immunogenic tumors in syngeneic mice. In this study, we examined whether B16F10 melanoma cells regressed with the elimination of CD25(+) regulatory T cells. We found the melanoma cells were not affected at all by in vivo anti-CD25 mAb administration alone but tumor rejection resulted in all mice when the administration was combined with IL-12 gene transfer to tumor cells. In vivo, depletion of natural killer (NK) cells or CD8(+) T cells cancelled the tumor rejection. NK-cell depletion allowed IL-12-transfected B16F10 melanoma (B16/IL-12) to grow from an early stage and resulted in a more rapid tumor growth of B16/IL-12 than that in mice without administration of anti-CD25 mAb. On the other hand, CD8(+) T-cell depletion did not affect the tumor growth in the early phase but allowed B16/IL-12 to grow in rather a late phase and resulted in almost the same degree of tumor growth as in mice without administration of anti-CD25 mAb. In a previous study, we showed that the elimination of CD4(+) T cells enhanced the antitumor effect of B16/IL-12 and induced vitiligo-like coat color alteration. Therefore, we also examined the frequency of the change to a vitiligo-like coat color in mice showing tumor rejection caused by CD25(+) T-cell elimination to compare with the mechanism enhancing the antitumor effects by cell elimination. The elimination of CD25(+) T cells did not induce vitiligo-like coat color changes, though that of CD4(+) T cells induced the change in 60% of mice. Furthermore, we confirmed that elimination of CD25(+) T cells did not affect the T-helper (Th) 1/Th2 cytokine profile, while that of CD4(+)T cells abrogated the Th2 cytokines (IL-4 and IL-10) and resulted in a Th1-dominant cytokine profile in the tumor-draining lymph nodes (TDLNs) of B16/IL-12-bearing mice. These results indicate that in vivo depletion of CD25(+) regulatory T cells is a potent useful adjuvant in immunotherapy of B16F10 melanoma, when combined with IL-12 gene transfer and that the enhancement of the antitumor effect by CD25(+) T-cell depletion is mediated through CD8(+) T cells and may differ from the enhancing mechanism caused by CD4(+) T-cell depletion.