Antibodies to CD40 induce a lethal cytokine cascade after syngeneic bone marrow transplantation
Antibodies to CD40 induce a lethal cytokine cascade after syngeneic bone marrow transplantation
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DOI：
10.1053/bbmt.2001.v7.pm11302547
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发表时间：
2001-01-01
影响因子：
4.3
通讯作者：
Murphy, WJ
中科院分区：
文献类型：
--
作者：
Hixon, JA;Blazar, BR;Murphy, WJ
通过抗体或配体的CD 40刺激已显示在体内和体外抑制多种肿瘤细胞的生长。在这项研究中，我们评估了CD 40刺激的影响，使用鼠激动性CD 40单克隆抗体（MoAb）（FGK 115）或可溶性重组鼠CD 40配体（srmCD 40 L）在致死辐射和非辐射BALB/c小鼠。在接受高达100 μ g激动剂抗CD 40单克隆抗体的非辐照动物中，未观察到CD 40刺激后的毒性。然而，低至10 μ g的激动性抗CD 40单克隆抗体诱导急性毒性，导致致死性照射动物在照射后4天的100%发病率。接受抗CD 40单克隆抗体的动物的组织学评价显示，小肠、结肠和盲肠出现严重肠病变，伴绒毛破坏、杯状细胞耗竭和隐窝增生。延迟抗CD 40单克隆抗体的给药或减少照射量导致生存率增加和病变严重程度降低。接受激动性抗CD 40的致死性辐照小鼠的血清细胞因子水平分析显示干扰素（IFN）-γ显著增加。与接受相同方案的野生型小鼠相比，给予激动性抗CD 40单克隆抗体的致死性辐照IFN-γ敲除小鼠的存活率和最小肠道病变显著增加，表明IFN-γ在这种毒性反应中起主要作用。这些结果表明，在致死性照射后使用激动性抗体的CD 40刺激导致影响肠道的致命的、马槟榔诱导的疾病。
CD40 stimulation, by either antibody or ligand, has been shown to inhibit the growth of a variety of neoplastic cells, both in vivo and in vitro. In this study, we assessed the effects of CD40 stimulation using a murine agonistic CD40 monoclonal antibody (MoAb) (FGK115) or a soluble recombinant murine CD40 ligand (srmCD40L) in both lethally irradiated and nonirradiated BALB/c mice. Toxicity after CD40 stimulation was not observed in nonirradiated animals receiving up to 100 mug of the agonist anti-CD40 MoAb. However, as little as 10 mug of the agonistic anti-CD40 MoAb induced acute toxicity resulting in 100% morbidity of lethally irradiated animals by 4 days after irradiation. Histological evaluation of animals receiving anti-CD40 MoAb revealed severe intestinal lesions with disruption of the villi, goblet cell depletion, and crypt hyperplasia of the small intestine, colon, and cecum. Delaying the administration of anti-CD40 MoAb or reducing the amount of irradiation given resulted in increased survival and less severe lesions. Analysis of serum cytokine levels in lethally irradiated mice receiving agonistic anti-CD40 showed a marked increase of interferon (IFN)-gamma. Lethally irradiated IFN-gamma knockout mice given the agonistic anti-CD40 MoAb demonstrated significant increases in survival and minimal gut lesions compared with wild-type mice receiving the same regimen, suggesting that IFN-gamma plays a major role in this toxic reaction. These results indicate that CD40 stimulation using agonistic antibodies following lethal irradiation leads to a fatal, cytokine-induced disease affecting the intestine.