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Studies on no-specifical immunoregulatory effects to the host by the addministration of newly activated-peptides derived from Toxoplasma lysate substance

弓形虫裂解物衍生的新激活肽对宿主的非特异性免疫调节作用的研究

基本信息

批准号：
03404013
负责人：
SUZUKI Naoyoshi
金额：
$ 18.05万
依托单位：
Obihiro University of Agriculture and Veterinary Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1994
项目状态：
已结题

项目摘要

An imunomodulator, such as TLA (Toxoplasma lysate antigens) was tested in the experiments. Growth of the tumor autoinduced by 20-methylcholanthrene (MC) in rats and mice was inhibited after intramuscular injection of TLA.The antitumor activity of TLA was most obvious in the early stage of tumor growth. When TLA was administered to rats before the appearance of tumor, tumor formation was delayd slightly. According to the immunohistological examination of tumor tisue with anti-Thy-1 antibody, the rats treated with TLA showed large Thy-1 positive or Lymphokine-Activated Killer (LAK) cells, whereas the untreated rats indicated only a few small Thy-1 positive or NK cells. In a series of these studies, TLA induces NK cells, cytotoxic T-lymphocytes and LAK cells in animals after injection, and the induction of these killer cells needs to exist in combination with macrophages and lymphocytes in in vivo. An activity unit in TLA was isolated now as TLA-H6E,and the inhibitory activation to the tu … More mor growth was significantly strong in comparison with others. Using the TLA-H6E monoclonal antibody, the structure of H6E is now making clear.Newly synthesized peptides of the activity units which were isolated from cytokines (lymphokines) as an immunoregulator, Obiopeptide, were examined in the effect of Toxoplasma chronically infected animals. Mice chronically infected with Toxoplasma were treated with Chclophosphamide (Cyp), Obiopeptide-1 (Obio-1) and/or anti-CD4 monoclonal antibody to determine the effect of these immunosuppressive agents on the cysts in the brain. In the brain of non-treated, and infected Cyp-Obi-1 treated mice, with HE staining or anti-Toxoplasma ABC labelling staining, large typically rounded tissue cysts were mostly detected, and in some regions dividing microcysts were also founded. In contrast, brain tissue from Cyp only or anti-CD4 treated infected mice had multiple degenerated cysts of varied sizes in some brain regions, as well as clusters of microcysts, however, such change was more striking in the anti-CD4 treated mice. Infected mice treated with a combination of Cyp and Obi-1 showed a significantly higher survival of 80% compared to 20% survival in mice treated with Cyp only. Percent neutrophilic leucocytes, monocytes and lymphocytes in mice treated with a combination of Obi-1 and anti-CD4, or Obi-1 and Cyp were higher compared to those groups treated with anti-CD4 antibody, or Cyp only. The increase in neutrophilic leucocyte and lymphocyte counts after a combined Cyp and Obi-1 treatment may, like wise, contribute to the induction of resistance in mice aginst Toxoplasma gondii. These results indidcate that reactivation of rupture of tissue cysts in mice treated with Cyp, chronicaly infected with Toxoplasma, might be mainly mediated by CD4 positive cells rather than other CD8, CD5 cells. Furthermore, the increase of neutrophilic leukocytes might contribute to the induction of the resistnce to Toxoplamsa in mice, after treatment with Obi-1 and Cyp in combination. However, these results seem to suggest that the reactivation or rupture of tissue cysts in mice chronically infected with Toxoplasma is not principally correlated with the death of Cyp treated mice. Less

在实验中测试了免疫调节剂，例如TLA（弓形虫裂解物抗原）。TLA肌肉注射对20-甲基胆蒽（MC）诱发的大、小鼠肿瘤生长均有抑制作用，其抑瘤作用在肿瘤生长早期最为明显。在肿瘤形成前给予TLA，肿瘤形成时间稍有延迟。用抗Thy-1抗体对肿瘤组织进行免疫组织化学检查，结果显示TLA治疗组有大量Thy-1阳性细胞或LAK细胞，而未治疗组仅有少量Thy-1阳性细胞或NK细胞。在一系列的这些研究中，TLA在注射后诱导动物体内的NK细胞、细胞毒性T淋巴细胞和LAK细胞，而这些杀伤细胞的诱导需要在体内与巨噬细胞和淋巴细胞联合存在。目前已分离出TLA中的一个活性单位TLA-H6 E， ...更多信息莫尔生长与其他相比显著强劲。利用TLA-H6 E单克隆抗体，阐明了H6 E的结构，并从细胞因子（淋巴因子）中分离出活性单位的新合成肽，作为免疫调节剂Obiopeptide，对弓形虫慢性感染动物的作用进行了研究。用环磷酰胺（Cyp）、Obio-1和/或抗CD_4单克隆抗体治疗弓形虫慢性感染小鼠，观察这些免疫抑制剂对弓形虫脑内包囊的影响。在未治疗和感染Cyp-Obi-1治疗的小鼠的脑中，用HE染色或抗弓形虫ABC标记染色，大多数检测到大的典型圆形组织囊肿，并且在一些区域中还发现分裂的微囊。相比之下，来自仅Cyp或抗CD 4治疗的感染小鼠的脑组织在某些脑区域中具有多个不同大小的变性囊肿，以及微囊肿簇，然而，这种变化在抗CD 4治疗的小鼠中更显著。用Cyp和Obi-1组合治疗的感染小鼠显示出80%的显著更高的存活率，而仅用Cyp治疗的小鼠的存活率为20%。与用抗CD 4抗体或仅用Cyp处理的那些组相比，用Obi-1和抗CD 4或Obi-1和Cyp的组合处理的小鼠中的嗜中性白细胞、单核细胞和淋巴细胞的百分比更高。Cyp和Obi-1联合治疗后，嗜中性白细胞和淋巴细胞计数的增加可能有助于诱导小鼠对弓形虫的抗性。结果提示，Cyp处理的弓形虫慢性感染小鼠组织包囊破裂后的再激活可能主要是由CD_4 ~+细胞介导的，而不是由其他CD_8、CD_5细胞介导的。Obi-1和Cyp联合治疗后，小鼠体内嗜中性白细胞的增加可能与诱导抗弓形虫有关。然而，这些结果似乎表明，在慢性感染弓形虫的小鼠中，组织包囊的再活化或破裂与Cyp处理的小鼠的死亡没有主要相关性。少