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Article(id=1212693337904169570, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212693337426018913, articleNumber=1001-2494(2024)20-1881-08, orderNo=null, doi=10.11669/cpj.2024.20.001, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1719244800000, receivedDateStr=2024-06-25, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1767058222508, onlineDateStr=2025-12-30, pubDate=1729526400000, pubDateStr=2024-10-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1767058222508, onlineIssueDateStr=2025-12-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1767058222508, creator=13701087609, updateTime=1767058222508, updator=13701087609, issue=Issue{id=1212693337426018913, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='20', pageStart='1881', pageEnd='1984', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1767058222394, creator=13701087609, updateTime=1767059439376, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1212698441885602499, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212693337426018913, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1212698441889796804, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212693337426018913, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1881, endPage=1888, ext={EN=ArticleExt(id=1212693338201965155, articleId=1212693337904169570, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Pre-Clinical Toxicity Evaluation Accompanied with Biodistribution of Mixed Activated Killer Immune Cells, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To evaluate the safety and biodistribution characteristics of mixed activated killer (MAK) immune cells derived from the blood of tumor patients in immunodeficient mice. METHODS Immunodeficient NOG mice were injected with MAK cells 9 times via the tail vein. The mice were observed continuously for 28 d after the last administration. The clinical symptoms, body weight, food intake, hematological and serum biochemical indexes, cytokine indexes and histopathological changes in mice were investigated. In the meanwhile, the distribution characteristics of MAK cells in peripheral blood and various tissues and organs were investigated. RESULTS MAK cells had no significant effect on clinical symptoms, the injection site, body weight and food intake in mice, and could increase the level of human interferon gamma in serum of mice. MAK cells could elevate lymphocytes%, monocytes%, white blood cells and decrease basophils% in peripheral blood. Mix cell aggregates were observed in most organs. Massive expansion of MAK cells was observed in most tissues of mice after administration of MAK cells for 28 d. CONCLUSION MAK cells could proliferate and induce immune responses in immunodeficient NOG mice without obvious toxic reactions. Given the above, the data of this study can provide a reference for the non-clinical safety evaluation of related products.

, correspAuthors=Xiaobing ZHOU, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Manman ZHAO, Lijun JIANG, Chao WANG, Guitao HUO, Hua JIANG, Liang BEN, Chao LI, Tiantian HOU, Sanlong WANG, Xingchao GENG, Xiaobing ZHOU), CN=ArticleExt(id=1212693339724497544, articleId=1212693337904169570, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=混合活化杀伤免疫细胞临床前毒性伴随生物分布研究, columnId=1212693338294239845, journalTitle=中国药学杂志, columnName=细胞治疗产品评价专栏, runingTitle=null, highlight=null, articleAbstract=

目的 评价肿瘤患者血液来源的混合活化杀伤(mixed activated killer,MAK)免疫细胞在免疫缺陷小鼠体内的安全性及生物分布特征。方法 使用免疫缺陷NOG小鼠,尾静脉注射给予MAK细胞9次,末次给药后持续观察28 d,考察小鼠临床症状、体质量和摄食量变化、血液学和血清生化指标、细胞因子指标和组织病理学变化特点,同时伴随考察MAK在外周血及各组织脏器分布特征。结果 MAK细胞对小鼠临床症状、注射部位、体质量和摄食量无明显影响,小鼠血清可检测到人源干扰素-γ,MAK细胞体外输注可导致小鼠外周血淋巴细胞百分比、单核细胞百分比、白细胞数升高,嗜碱性粒细胞百分比降低,全身多数组织脏器可见混合细胞聚集。给予MAK细胞28 d后,小鼠全身多数组织出现MAK细胞的大量扩增。结论 MAK细胞在免疫缺陷NOG小鼠体内增殖并引起机体免疫应答反应,未见明显毒性反应风险。本研究数据可为相关产品非临床安全性评价提供借鉴。

, correspAuthors=周晓冰, authorNote=null, correspAuthorsNote=
* 周晓冰,女,博士,研究员 研究方向:药物毒理学研究 Tel:(010)67872233-8203
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赵曼曼,女,博士,主管药师 研究方向:药物毒理学研究

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赵曼曼,女,博士,主管药师 研究方向:药物毒理学研究

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赵曼曼,女,博士,主管药师 研究方向:药物毒理学研究

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Beijing: Chinese Academy of Medical Sciences Peking Union Medical College, 2020., articleTitle=null, refAbstract=null), Reference(id=1212799320341005109, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, doi=null, pmid=null, pmcid=null, year=2022, volume=45, issue=8, pageStart=840, pageEnd=845, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=ZHU L Y, CHEN X, SHI Y, journalName=Chin J Lab Med(中华检验医学杂志), refType=null, unstructuredReference=ZHU L Y, CHEN X, SHI Y, et al. The monitoring value of twelve inflammatory cytokines in chimeric antigen receptor T cell immunotherapy[J]. Chin J Lab Med(中华检验医学杂志), 2022, 45(8):840-845., articleTitle=The monitoring value of twelve inflammatory cytokines in chimeric antigen receptor T cell immunotherapy, refAbstract=null), Reference(id=1212799320412308280, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, doi=null, pmid=null, pmcid=null, year=2021, volume=37, issue=2, pageStart=268, pageEnd=271, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=SHI Y Q, YU Y H, journalName=J Pract Med(实用医学杂志), refType=null, unstructuredReference=SHI Y Q, YU Y H. Current status and prospects of CAR-T cell therapy for cytokine release syndrome and neurotoxicity[J]. J Pract Med(实用医学杂志), 2021, 37(2):268-271., articleTitle=Current status and prospects of CAR-T cell therapy for cytokine release syndrome and neurotoxicity, refAbstract=null), Reference(id=1212799320492000059, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, doi=null, pmid=null, pmcid=null, year=2013, volume=null, issue=null, pageStart=null, pageEnd=null, url=https://www.fda.gov/media/87564/download, language=null, rfNumber=[15], rfOrder=14, authorNames=US Food, Drug Administration, journalName=null, refType=null, unstructuredReference=US Food and Drug Administration. Guidance for industry: preclinical assessment of investigational cellular and gene therapy products[EB/OL]. (2013-11) [2022-08-17]. https://www.fda.gov/media/87564/download., articleTitle=Guidance for industry: preclinical assessment of investigational cellular and gene therapy products, refAbstract=null), Reference(id=1212799320567497537, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, doi=null, pmid=null, pmcid=null, year=2021, volume=35, issue=8, pageStart=624, pageEnd=631, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=WANG S Z, XU B H, WANG Y, journalName=Chin J Pharm Toxicol(中国药理学与毒理学杂志), refType=null, unstructuredReference=WANG S Z, XU B H, WANG Y, et al. Research progress in preclinical in vivo tracer technology for cell therapy products[J]. Chin J Pharm Toxicol(中国药理学与毒理学杂志), 2021, 35(8):624-631., articleTitle=Research progress in preclinical in vivo tracer technology for cell therapy products, refAbstract=null)], funds=[Fund(id=1212799317950251776, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, awardId=2021YFA1101602, language=CN, fundingSource=国家重点研发计划课题资助(2021YFA1101602), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1212799309431620047, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, xref=1, ext=[AuthorCompanyExt(id=1212799309440008656, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, companyId=1212799309431620047, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs, Institute for Safety Evaluation, National Institutes for Food and Drug Control, Beijing 100176, China), AuthorCompanyExt(id=1212799309448397265, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, companyId=1212799309431620047, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 中国食品药品检定研究院安全评价研究所, 药物非临床安全评价研究北京市重点实验室, 北京 100176)]), AuthorCompany(id=1212799309515506132, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, xref=2, ext=[AuthorCompanyExt(id=1212799309519700438, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, companyId=1212799309515506132, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 Tuohua Bio-technology Co., Ltd., Siping 136001, China), AuthorCompanyExt(id=1212799309528089046, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, companyId=1212799309515506132, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 吉林省拓华生物科技有限公司, 吉林 四平 136001)])], figs=[ArticleFig(id=1212799316108952258, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Fig.1, caption=Body weight and food consumption of mice after MAK cells administration. $\stackrel{-}{x}$±s

A-body weight of male mice(n=5~15); B-body weight of female mice(n=5~15); C-food consumption of male mice(n=5); D-food consumption of female mice(n=5); 1)P<0.05, compared with the vehicle Control group.

, figureFileSmall=6efdt4uwMgPLlvCdTuopaw==, figureFileBig=9fsH7RvaoHFDuq86OQdbvQ==, tableContent=null), ArticleFig(id=1212799316192838340, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=图1, caption=给予MAK细胞后动物体质量及摄食量测定结果。$\stackrel{-}{x}$±s

A-雄鼠体质量(n=5~15);B-雌鼠体质量(n=5~15);C-雄鼠摄食量(n=5);D-雌鼠摄食量(n=5);与溶媒对照组比较, 1)P<0.05。

, figureFileSmall=6efdt4uwMgPLlvCdTuopaw==, figureFileBig=9fsH7RvaoHFDuq86OQdbvQ==, tableContent=null), ArticleFig(id=1212799316335444681, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Fig.2, caption=Changes of major hematological indexes of mice after MAK cells administration. $\stackrel{-}{x}$±s

A-blood cell counts of male mice at the end of administration (n=10); B-blood cell counts of female mice at the end of administration(n=10); C-blood cell counts of male mice at the end of recovery(n=5); D-blood cell counts of female mice at the end of recovery(n=5); E-differential percentage of leukocytes of male mice at the end of administration(n=10); F-differential percentage of leukocytes of female mice at the end of administration(n=10); G-differential percentage of leukocytes of male mice at the end of recovery(n=5); H-differential percentage of leukocytes of female mice at the end of recovery(n=5); WBC-white blood cell; RBC-red blood cell; PLT-platelet; NEUT-neutrophil; LYMP-lymphocyte; MONO-monocyte; BASO-basophil; 1)P<0.05, 2)P<0.01, compared with the vehicle Control group.

, figureFileSmall=wr+N0wQt2Hz9y1WIaphI5w==, figureFileBig=GIZ40mH0V38Z0HGNebrCUQ==, tableContent=null), ArticleFig(id=1212799316423525070, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=图2, caption=给予MAK细胞后动物主要血液学指标变化。$\stackrel{-}{x}$±s

A-给药结束雄鼠血细胞计数结果(n=10);B-给药结束雌鼠血细胞计数结果(n=10);C-恢复结束雄鼠血细胞计数结果(n=5);D-恢复结束雌鼠血细胞计数结果(n=5);E-给药结束雄鼠白细胞分类百分比(n=10);F-给药结束雌鼠白细胞分类百分比(n=10);G-恢复结束雄鼠白细胞分类百分比(n=5);H-恢复结束雌鼠白细胞分类百分比(n=5);WBC-白细胞;RBC-红细胞;PLT-血小板;NEUT-中性粒细胞;LYMP-淋巴细胞;MONO-单核细胞;BASO-嗜碱性粒细胞;与溶媒对照组比较, 1)P<0.05, 2)P<0.01。

, figureFileSmall=wr+N0wQt2Hz9y1WIaphI5w==, figureFileBig=GIZ40mH0V38Z0HGNebrCUQ==, tableContent=null), ArticleFig(id=1212799316499022546, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Fig.3, caption=Changes of major serum biochemistry indexes of mice after MAK cells administration. $\stackrel{-}{x}$±s

A-serum biochemical results of male mice at the end of administration (n=10); B-serum biochemical results of female mice at the end of administration (n=10); C-serum biochemical results of male mice at the end of recovery (n=5); D-serum biochemical results of female mice at the end of recovery (n=5); ALT-alanine aminotransferase; AST-aspartate aminotransferase; ALP-alkaline phosphatase;CK-creatine kinase;LDH-lactate dehydrogenase; 1)P<0.05, compared with the vehicle Control group.

, figureFileSmall=sdNiv9kkFA6NzuYWJ0ew4g==, figureFileBig=d6G9XiMInV0h+SBM9RyBYA==, tableContent=null), ArticleFig(id=1212799316587102934, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=图3, caption=给予MAK细胞后动物主要血清生化指标的变化。$\stackrel{-}{x}$±s

A-给药结束雄鼠血清生化结果(n=10);B-给药结束雌鼠血清生化结果(n=10);C-恢复结束雄鼠血清生化结果(n=5);D-恢复结束雌鼠血清生化结果(n=5);ALT-丙氨酸氨基转移酶;AST-门冬氨酸氨基转移酶;ALP-碱性磷酸酶;CK-肌酸激酶;LDH-乳酸脱氢酶;与溶媒对照组比较, 1)P<0.05。

, figureFileSmall=sdNiv9kkFA6NzuYWJ0ew4g==, figureFileBig=d6G9XiMInV0h+SBM9RyBYA==, tableContent=null), ArticleFig(id=1212799316679377626, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Fig.4, caption=Typical histopathological changes associated with MAK administration (HE staining, ×200)

A-moderate mixed cells aggregation in lung; B-moderate mixed cells aggregation in spleen; C-mild mixed cells aggregation in liver; D-minimal mixed cells aggregation in heart; E-minimal mixed cells aggregation in kidney; F-moderate mixed cells aggregation in thyroid; G-mild mixed cells aggregation, mild squamous cells hyperplasia and very mild basal cell degeneration/necrosis in forestomach; H-minimal mixed cells aggregation in pituitary gland; I-mild mixed cells aggregation in skin; J-mild mixed cells aggregation in fallopian tube; K-minimal mixed cells aggregation in epididymis.

, figureFileSmall=e6/qS54ExpDpYdoZLjRlRA==, figureFileBig=vVTxXqUUt6tJGlgfBkthJg==, tableContent=null), ArticleFig(id=1212799316792623834, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=图4, caption=与MAK细胞有关的组织病理学改变(HE 染色,×200)

A-肺脏中度混合细胞聚集;B-脾脏中度混合细胞聚集;C-肝脏轻度混合细胞聚集;D-心脏极轻度混合细胞聚集;E-肾脏极轻度混合细胞聚集;F-甲状腺中度混合细胞聚集;G-前胃轻度混合细胞聚集、轻度鳞状细胞增生及极轻度基底细胞变性/坏死;H-垂体极轻度混合细胞聚集;I-皮肤轻度混合细胞聚集;J-输卵管轻度混合细胞聚集;K-附睾极轻度混合细胞聚集。

, figureFileSmall=e6/qS54ExpDpYdoZLjRlRA==, figureFileBig=vVTxXqUUt6tJGlgfBkthJg==, tableContent=null), ArticleFig(id=1212799316985561825, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Fig.5, caption=Content of MAK cells in blood of mice after MAK cells administration. n=5,$\stackrel{-}{x}$±s

A-content of MAK cells in blood of male mice; B-content of MAK cells in blood of female mice.

, figureFileSmall=8h2Udz1+PqCifx49rOKUvQ==, figureFileBig=2IZEG2xqI8gMzzz4gJMB7A==, tableContent=null), ArticleFig(id=1212799317086225125, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=图5, caption=给予MAK细胞后动物血液中MAK含量。n=5,$\stackrel{-}{x}$±s

A-雄性动物血液中MAK细胞水平变化;B-雌性动物血液中MAK细胞水平变化。

, figureFileSmall=8h2Udz1+PqCifx49rOKUvQ==, figureFileBig=2IZEG2xqI8gMzzz4gJMB7A==, tableContent=null), ArticleFig(id=1212799317212054249, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Fig.6, caption=DNA content of MAK cells in organs of mice after MAK cells administration. n=5,$\stackrel{-}{x}$±s

A-DNA content of MAK cells of male mice at the end of administration; B-DNA content of MAK cells of female mice at the end of administration; C-DNA content of MAK cells of male mice at the end of recovery; D-DNA content of MAK cells of female mice at the end of recover.

, figureFileSmall=uHUHnwzv1xMeXHU1WFwsvA==, figureFileBig=3xEmuZJ9i6+Ot75vQK31vA==, tableContent=null), ArticleFig(id=1212799317321106158, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=图6, caption=给予MAK细胞后动物动物各脏器MAK细胞DNA含量。n=5,$\stackrel{-}{x}$±s

A-给药结束雄鼠各脏器MAK细胞DNA含量;B-给药结束雌鼠各脏器MAK细胞DNA含量;C-恢复结束雄鼠各脏器MAK细胞DNA含量;D-恢复结束雌鼠各脏器MAK细胞DNA含量。

, figureFileSmall=uHUHnwzv1xMeXHU1WFwsvA==, figureFileBig=3xEmuZJ9i6+Ot75vQK31vA==, tableContent=null), ArticleFig(id=1212799317388215023, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Tab.1, caption=

Study design of pre-clinical toxicity evaluation of mixed activated killer(MAK) cells

, figureFileSmall=null, figureFileBig=null, tableContent=
Groups Test
articles		 Concentration
/cells·mL-1		 Dose
/cells·kg-1		 Volume
/mL·kg-1		 n
(♀/♂)		 Necropsy
period		 Content of
evaluation
Main Vehicle control Vehicle 0 0 15 15/15 End of administration, end of recovery General toxicity, hematology, serum biochemistry, cytokines, and histopathology
Low MAK 2.67×107 4×108 15 15/15
High MAK 1.07×108 16×108 15 15/15
Satellite Vehicle control Vehicle 0 0 15 6/6 End of administration, end of recovery MAK cells in blood (3 h, 24 h, 3 d, 7 d, 14 d and 28 d),biodistribution analysis by qPCR
Low MAK 2.67×107 4×108 15 10/10
High MAK 1.07×108 16×108 15 10/10
), ArticleFig(id=1212799317488878322, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=表1, caption=

混合活化杀伤(MAK)细胞临床前毒性评价的试验设计概况

, figureFileSmall=null, figureFileBig=null, tableContent=
Groups Test
articles		 Concentration
/cells·mL-1		 Dose
/cells·kg-1		 Volume
/mL·kg-1		 n
(♀/♂)		 Necropsy
period		 Content of
evaluation
Main Vehicle control Vehicle 0 0 15 15/15 End of administration, end of recovery General toxicity, hematology, serum biochemistry, cytokines, and histopathology
Low MAK 2.67×107 4×108 15 15/15
High MAK 1.07×108 16×108 15 15/15
Satellite Vehicle control Vehicle 0 0 15 6/6 End of administration, end of recovery MAK cells in blood (3 h, 24 h, 3 d, 7 d, 14 d and 28 d),biodistribution analysis by qPCR
Low MAK 2.67×107 4×108 15 10/10
High MAK 1.07×108 16×108 15 10/10
), ArticleFig(id=1212799317589541622, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=EN, label=Tab.2, caption=

Content of cytokines in mice after MAK cells administration. $\stackrel{-}{x}$±s

, figureFileSmall=null, figureFileBig=null, tableContent=
Sex Groups End of administration
n IFN-γ/pg·mL-1 TNF/pg·mL-1 IL-10/pg·mL-1 IL-6/pg·mL-1
Female Vehicle Control 10 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Low 10 2.18 ±3.83 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
High 10 26.81 ±28.992) 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Male Vehicle Control 10 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.88 ±1.44
Low 9 1.35 ±2.04 0.00 ±0.00 0.00 ±0.00 0.61 ±1.22
High 10 47.42 ±76.612) 0.00 ±0.00 0.81 ±2.57 0.00 ±0.00
Sex Groups End of recovery
n IFN-γ/pg·mL-1 TNF/pg·mL-1 IL-10/pg·mL-1 IL-6/pg·mL-1
Female Solvent Control 4 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Low 5 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
High 5 647.03 ±640.891) 0.00 ±0.00 4.75 ±4.50 0.00 ±0.00
Male Solvent Control 5 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Low 4 149.78 ±285.142) 0.00 ±0.00 11.05 ±22.112) 0.00 ±0.00
High 5 1 054.61 ±1 011.052) 4.53 ±4.78 21.36 ±27.192) 1.71 ±3.822)
), ArticleFig(id=1212799317681816313, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212693337904169570, language=CN, label=表2, caption=

给予MAK细胞后动物细胞因子水平。$\stackrel{-}{x}$±s

, figureFileSmall=null, figureFileBig=null, tableContent=
Sex Groups End of administration
n IFN-γ/pg·mL-1 TNF/pg·mL-1 IL-10/pg·mL-1 IL-6/pg·mL-1
Female Vehicle Control 10 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Low 10 2.18 ±3.83 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
High 10 26.81 ±28.992) 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Male Vehicle Control 10 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.88 ±1.44
Low 9 1.35 ±2.04 0.00 ±0.00 0.00 ±0.00 0.61 ±1.22
High 10 47.42 ±76.612) 0.00 ±0.00 0.81 ±2.57 0.00 ±0.00
Sex Groups End of recovery
n IFN-γ/pg·mL-1 TNF/pg·mL-1 IL-10/pg·mL-1 IL-6/pg·mL-1
Female Solvent Control 4 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Low 5 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
High 5 647.03 ±640.891) 0.00 ±0.00 4.75 ±4.50 0.00 ±0.00
Male Solvent Control 5 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00 0.00 ±0.00
Low 4 149.78 ±285.142) 0.00 ±0.00 11.05 ±22.112) 0.00 ±0.00
High 5 1 054.61 ±1 011.052) 4.53 ±4.78 21.36 ±27.192) 1.71 ±3.822)
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混合活化杀伤免疫细胞临床前毒性伴随生物分布研究
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赵曼曼 1 , 姜丽君 2 , 王超 1 , 霍桂桃 1 , 姜华 1 , 贲亮 2 , 李超 2 , 侯田田 1 , 王三龙 1 , 耿兴超 1 , 周晓冰 1, *
中国药学杂志 | 细胞治疗产品评价专栏 2024,59(20): 1881-1888
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中国药学杂志 | 细胞治疗产品评价专栏 2024, 59(20): 1881-1888
混合活化杀伤免疫细胞临床前毒性伴随生物分布研究
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赵曼曼1, 姜丽君2, 王超1, 霍桂桃1, 姜华1, 贲亮2, 李超2, 侯田田1, 王三龙1, 耿兴超1, 周晓冰1, *
作者信息
  • 1 中国食品药品检定研究院安全评价研究所, 药物非临床安全评价研究北京市重点实验室, 北京 100176
  • 2 吉林省拓华生物科技有限公司, 吉林 四平 136001

    • 赵曼曼,女,博士,主管药师 研究方向:药物毒理学研究

通讯作者:

* 周晓冰,女,博士,研究员 研究方向:药物毒理学研究 Tel:(010)67872233-8203
Pre-Clinical Toxicity Evaluation Accompanied with Biodistribution of Mixed Activated Killer Immune Cells
Manman ZHAO1, Lijun JIANG2, Chao WANG1, Guitao HUO1, Hua JIANG1, Liang BEN2, Chao LI2, Tiantian HOU1, Sanlong WANG1, Xingchao GENG1, Xiaobing ZHOU1, *
Affiliations
  • 1 Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs, Institute for Safety Evaluation, National Institutes for Food and Drug Control, Beijing 100176, China
  • 2 Tuohua Bio-technology Co., Ltd., Siping 136001, China
出版时间: 2024-10-22 doi: 10.11669/cpj.2024.20.001
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摘要
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目的 评价肿瘤患者血液来源的混合活化杀伤(mixed activated killer,MAK)免疫细胞在免疫缺陷小鼠体内的安全性及生物分布特征。方法 使用免疫缺陷NOG小鼠,尾静脉注射给予MAK细胞9次,末次给药后持续观察28 d,考察小鼠临床症状、体质量和摄食量变化、血液学和血清生化指标、细胞因子指标和组织病理学变化特点,同时伴随考察MAK在外周血及各组织脏器分布特征。结果 MAK细胞对小鼠临床症状、注射部位、体质量和摄食量无明显影响,小鼠血清可检测到人源干扰素-γ,MAK细胞体外输注可导致小鼠外周血淋巴细胞百分比、单核细胞百分比、白细胞数升高,嗜碱性粒细胞百分比降低,全身多数组织脏器可见混合细胞聚集。给予MAK细胞28 d后,小鼠全身多数组织出现MAK细胞的大量扩增。结论 MAK细胞在免疫缺陷NOG小鼠体内增殖并引起机体免疫应答反应,未见明显毒性反应风险。本研究数据可为相关产品非临床安全性评价提供借鉴。

混合活化杀伤免疫细胞  /  免疫缺陷小鼠  /  毒性评价  /  生物分布

OBJECTIVE To evaluate the safety and biodistribution characteristics of mixed activated killer (MAK) immune cells derived from the blood of tumor patients in immunodeficient mice. METHODS Immunodeficient NOG mice were injected with MAK cells 9 times via the tail vein. The mice were observed continuously for 28 d after the last administration. The clinical symptoms, body weight, food intake, hematological and serum biochemical indexes, cytokine indexes and histopathological changes in mice were investigated. In the meanwhile, the distribution characteristics of MAK cells in peripheral blood and various tissues and organs were investigated. RESULTS MAK cells had no significant effect on clinical symptoms, the injection site, body weight and food intake in mice, and could increase the level of human interferon gamma in serum of mice. MAK cells could elevate lymphocytes%, monocytes%, white blood cells and decrease basophils% in peripheral blood. Mix cell aggregates were observed in most organs. Massive expansion of MAK cells was observed in most tissues of mice after administration of MAK cells for 28 d. CONCLUSION MAK cells could proliferate and induce immune responses in immunodeficient NOG mice without obvious toxic reactions. Given the above, the data of this study can provide a reference for the non-clinical safety evaluation of related products.

mixed activated killer (MAK) immune cell  /  immunodeficient mice  /  toxicity evaluation  /  biodistribution
赵曼曼, 姜丽君, 王超, 霍桂桃, 姜华, 贲亮, 李超, 侯田田, 王三龙, 耿兴超, 周晓冰. 混合活化杀伤免疫细胞临床前毒性伴随生物分布研究. 中国药学杂志, 2024 , 59 (20) : 1881 -1888 . DOI: 10.11669/cpj.2024.20.001
Manman ZHAO, Lijun JIANG, Chao WANG, Guitao HUO, Hua JIANG, Liang BEN, Chao LI, Tiantian HOU, Sanlong WANG, Xingchao GENG, Xiaobing ZHOU. Pre-Clinical Toxicity Evaluation Accompanied with Biodistribution of Mixed Activated Killer Immune Cells[J]. Chinese Pharmaceutical Journal, 2024 , 59 (20) : 1881 -1888 . DOI: 10.11669/cpj.2024.20.001
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细胞治疗是指利用某些具有特定功能的细胞的特性,采用生物工程方法获取和/或通过体外扩增、特殊培养等处理后,使这些细胞具有增强免疫、杀死病原体和肿瘤细胞、促进组织器官再生和机体康复等治疗功效,从而达到治疗疾病目的的疗法。作为一种里程碑式的新型治疗手段,细胞治疗突破了传统药物治疗的局限,为癌症等疾病提供了全新的治疗思路和途径,已经成为中国医药健康产业重点发展的新赛道之一。免疫细胞治疗是中国细胞治疗产业规模最大的领域,目前中国已有6款嵌合抗原受体T细胞(CAR-T)产品上市。近几年,我国一直致力于加强细胞治疗产品的技术创新与规范发展,国家药监局发布了《细胞治疗产品研究与评价技术指导原则(试行)》《基因修饰细胞治疗产品非临床研究技术指导原则(试行)》等系列技术指导原则,旨在不断完善细胞治疗行业监管,推动行业健康快速发展。
对于细胞治疗产品,临床前评价依然是提供有效性、安全性信息的重要依据。与传统的小分子化学药物、大分子生物技术药物相比,细胞治疗产品的物质组成及作用机制特殊,细胞的来源、类型、性质、功能、生产工艺、非细胞成分、非目的细胞群体、全生产过程中的污染等是引起细胞治疗产品安全性风险的重要因素,此外,由于细胞治疗产品技术发展迅速、性质复杂多变,因此细胞治疗产品临床前研究的方法和策略面临更多的挑战。
为此,本期设置“细胞治疗产品评价专栏”,旨在介绍CAR-T、自然杀伤细胞/自然杀伤T细胞(NK/NKT)、细胞因子诱导的杀伤细胞(CIK)、肿瘤浸润淋巴细胞(TIL)等细胞治疗产品的毒理学研究,这些研究将为建立细胞治疗产品等先进治疗产品临床前毒理学评价体系提供基础数据,为开展先进治疗产品毒理学研究提供参考。
[学术策划 李波、耿兴超、周晓冰; 专栏编辑 曹泱]
肿瘤是我国的重大公共卫生问题。目前,我国恶性肿瘤发病、死亡数持续上升,并且随着人口老龄化的加剧,我国癌症负担将逐步加重[1]。随着细胞治疗基础理论与技术的不断发展,免疫细胞治疗为恶性肿瘤治疗提供了新的思路和方法[2-4]。自然杀伤(natural killer,NK)细胞作为一种极具潜力的过继性细胞治疗平台,在改善肿瘤治疗方面受到了广泛关注[5]。混合活化杀伤(mixed activated killer,MAK)免疫细胞是一种以NK 细胞、自然杀伤T(natural killer T,NKT)细胞为主的免疫细胞群,具有高效肿瘤杀伤活性,在临床上作为一种过继性免疫细胞疗法用于恶性肿瘤治疗。
根据2017年我国发布的《细胞治疗产品研究与评价技术指导原则(试行)》[6],毒理学试验设计应基于产品治疗原理、体内生物学行为和临床应用特点采用具体问题具体分析原则。基于MAK细胞人源性特点,选择免疫缺陷动物作为实验动物模型[7-8]。为更好阐明MAK安全性特征,还需动态观察MAK细胞在动物体内分布及存续情况[9]。本研究采用重度免疫缺陷NOG小鼠,静脉注射给予MAK细胞,全面考察了MAK细胞对NOG小鼠的毒性反应及严重程度,同时考察MAK细胞在动物体内的分布情况,为其临床研究提供参考依据。
1 仪器与材料
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1.1 动物
6~7周龄无特定病原体(specific pathogen-free,SPF)级NOG小鼠142只,其中雌性71只(体质量15.0~18.3 g)、雄性71只(体质量17.8~21.6 g),动物来源为北京维通利华实验动物技术有限公司,动物生产许可证编号为SCXK(京)2021-0006,雄、雌动物合格证号分别为110011211111964073、110011211111963913。全部动物饲养于安全评价研究所屏障动物房内,环境条件为温度20~26 ℃、日温差≤3 ℃、相对湿度40%~70%、照明时间12 h·d-1。动物适应性饲养6 d,自由饮食、饮水。本研究方案通过安全评价研究所实验动物福利伦理委员会审查(伦理审查编号:IACUC-2021-094)。
1.2 材料
MAK细胞(批号:C-Pb20211003069、C-Pb20211010069、C-Pb20211017069),溶媒(成分为2%人血白蛋白溶液,批号:RM20211024001,吉林省拓华生物科技有限公司)。
1.3 仪器
小动物活体成像仪(IVIS Lumina Ⅲ,美国Perkin Elmer 公司);包埋机(TEC5,日本Sakura 公司);染色机(DRS-Prisma-P-JCS, 日本Sakura 公司);封片机(Film-JC2,日本Sakura 公司);流式细胞计数仪(FACS Calibur,美国BD 公司);荧光实时定量PCR仪(ABI 7500,美国Applied Biosystems公司);综合血液学检查装置(XN-550,日本Sysmex公司);血凝分析仪(CA-1500,日本Sysmex公司);全自动生化分析仪(7180,日本日立公司);天平(PB 203-N,瑞士梅特勒公司)。
2 方法
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2.1 实验动物分组及给药
142只NOG小鼠按照雌、雄分组,同性别小鼠再分为主试验组和卫星组,主试验组进行毒性指标检测,卫星组进行伴随生物分布研究。主试验组及卫星组分别设置溶媒对照组、低剂量组(每千克4×108个MAK细胞)和高剂量组(每千克16×108个MAK细胞),其中低剂量与临床人拟用剂量相当,高剂量为临床人拟用剂量4倍(按体表面积折算)。主试验组每组15只,卫星组6或10只。尾静脉注射给予溶媒或MAK细胞,D1~D3、D8~D10、D16~D18给药,每天1次,共9次,给药结束后恢复28 d。试验设计概况见表1。
2.2 观察和检测指标
对主试验组动物进行临床症状观察及注射部位观察,定期测定动物的体质量和摄食量,在末次给药后每组解剖10只,恢复期结束解剖剩余5只,进行血液学、血清生化及细胞因子指标测定,取主要脏器进行组织病理学检查。
卫星组动物在首次给药前、首次给药后、末次给药前和末次给药后不同时间点采血(3、24 h、3、7、14和28 d),血液经肝素钠抗凝,充分摇匀,使用流式细胞仪测定血液中CD3-CD16+CD56+细胞和CD3+CD56+细胞数量(二者之和即为MAK细胞数量)。在末次给药后及恢复期结束后,卫星组动物(对照组雌雄各3只、给药组雌雄各5只)异氟烷麻醉后从腹腔后大静脉采血,采血后使用生理盐水对动物进行全身灌流,摘取心脏、肝脏、脾脏、肺脏、肾脏、脑、子宫/睾丸、卵巢/附睾、胃、十二指肠、结肠、骨髓、脂肪、骨骼肌,置于-80 ℃冰箱保存。测定时,首先提取血液及各组织样本DNA,测定提取的DNA的浓度及纯度,样本质量浓度稀释至约50 ng·μL-1,低于50 ng·μL-1的样本则不再调整。qPCR扩增体系总体积为20 μL,反应条件为预变性95 ℃ 5 min,PCR反应95 ℃ 10 s、62 ℃ 50 s,循环数40,上游引物和下游引物序列分别为5'-TGCACGCGATAGCATTGC-3'、5'-AGGCAGGAATCAAAGACAGATACTG-3',探针序列为5'-FAM-CGCTGGAGCCGGAGCACCC-BHQ-3'。
2.3 统计学处理
临床症状和注射部位观察结果直接列出。体质量、摄食量、血液学指标、血清生化指标及细胞因子指标用$\stackrel{-}{x}$±s表示,采用单因素方差分析,P<0.05表示差异有统计学意义。
3 结果
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3.1 临床症状及注射部位观察
试验期间,除主试验组低剂量组2只雄性动物死亡外,其他动物临床症状均未见异常。其中1只死亡动物大体剖检可见脾脏体积增大,镜检可见多个脏器混合细胞聚集,肝脏轻度肝细胞坏死,不排除其死因与给予MAK细胞有关。另外1只死亡动物大体剖检及镜检均未见异常。此外,各组动物注射部位均未见出血、发红、肿胀、硬结、化脓、坏死等异常,提示给予MAK细胞对注射部位无明显影响。
3.2 体质量及摄食量
体质量及摄食量测定结果见图1。试验期间,各组动物体质量呈增长趋势。给药期间,各组动物体质量未见统计学差异;恢复期间,与溶媒对照组比,各组雄性动物体质量未见统计学差异,低剂量及高剂量组雌性动物体质量略低,个别时间点出现统计学差异,但未见体质量持续下降,认为该变化与给予MAK细胞无关。以上结果提示MAK细胞对小鼠体质量无明显影响。
与溶媒对照组比,各给药组动物的摄食量均未见明显变化。
3.3 血液学指标
不同时间点各组动物血液学指标变化见图2。给药结束,与溶媒对照组相比,高剂量组雄性动物淋巴细胞百分比(LYMP%)(P<0.01)、单核细胞百分比(MONO%)(P<0.01)及嗜碱性粒细胞百分比(BASO%)(P<0.01)升高;恢复期结束,高剂量组雄性动物LYMP%、MONO%呈现升高趋势,BASO%呈现降低趋势,同时高剂量组雄性动物白细胞数(WBC)升高(P<0.05)。给药结束及恢复期结束,雌性动物高剂量组也出现LYMP%、MONO%、WBC升高趋势及BASO%降低趋势。
给药结束,低剂量组雌性动物血小板数(PLT)升高(P<0.05),高剂量组雌性动物上述指标未见明显变化,剂量-反应关系不明显,认为该变化无毒理学意义。
3.4 血清生化指标
不同时间点各组动物血清生化指标变化见图3。给药结束,与溶媒对照组相比,低剂量组雄性动物门冬氨酸氨基转移酶(AST)降低(P<0.01),高剂量组雄性动物AST未见明显变化,认为低剂量组AST降低无毒理学意义。其他动物各给药组间血清生化指标未见统计学差异。
3.5 人源细胞因子检测
不同时间点各组动物血清中人源细胞因子水平见表2。给药结束,与溶媒对照组相比,高剂量组动物干扰素-γ(IFN-γ)水平显著升高,且随着给药后时间延长,IFN-γ水平持续增加。个别动物可检测到较低水平的肿瘤坏死因子(TNF)、白细胞介素-10(IL-10)、白细胞介素-6(IL-6)。该结果表明,给予MAK细胞后可在小鼠血清中检测到人源细胞因子IFN-γ、TNF、IL-10、IL-6,其中IFN-γ水平增加显著,且随给药后时间延长,细胞因子水平呈升高趋势,这可能与MAK细胞在小鼠体内增殖及发挥药理学作用有关。
3.6 组织病理学改变
对NOG小鼠主要脏器进行组织病理学检查,结果见图4,与给予MAK细胞有关的主要病理学改变涉及多个脏器[包括心脏、主动脉、肺(含支气管)、肝脏、脾脏、胰腺、颌下腺、舌下腺、肾脏、胃、甲状腺、舌、气管、食管、坐骨神经、附睾、前列腺、精囊腺、垂体、脑、子宫(含子宫颈)、阴道、卵巢、输卵管、膀胱、注射部位、肾上腺、肌肉(骨骼肌)、哈氏腺、皮肤]混合细胞聚集,聚集的细胞主要是MAK细胞和给予细胞后增生的各种免疫相关细胞(以单核巨噬细胞和粒细胞为主)组成。考虑上述脏器所见混合细胞聚集的情况体现了MAK细胞在实验动物体内的增殖及诱导其他免疫相关细胞增殖的过程,是其发挥药效学作用的表现,提示临床试验时需予以关注。
3.7 MAK细胞生物分布
流式细胞术检测血液中MAK细胞数量的结果见图5。用流式细胞仪收集5 000个细胞,计数CD3-CD16+CD56+细胞和CD3+CD56+细胞数量(二者之和即为MAK细胞数量)。MAK细胞在雌、雄动物血液中的变化趋势类似。首次给药后3 h血液中即可检测到MAK细胞,末次给药前血液中MAK细胞数达到最高。末次给药后3 h细胞数降低,24 h后逐渐升高,至给药后3 d达最高,后逐渐降低,在给药后28 d低剂量组动物血液中几乎检测不到MAK细胞,此时高剂量组动物仍可检测到一定水平的MAK细胞。
实时定量聚合酶链反应(qPCR)方法检测组织中MAK细胞DNA水平的结果见图6。给药结束,低、高剂量组雌性和雄性动物血液、子宫、睾丸、卵巢、附睾、肾脏、肝脏、脾脏、肺脏、心脏、脑、胃、十二指肠、结肠、骨髓、脂肪、骨骼肌(低剂量组子宫除外)均检测到MAK细胞线粒体基因,且呈剂量依赖性增加。其中脾脏、肺脏、肾脏和肝脏基因拷贝数最高,其他组织基因拷贝水平较低。恢复期结束,雌性和雄性动物血液和组织中MAK细胞线粒体基因拷贝水平显著增加,提示此时全身多数组织出现了MAK细胞的大量扩增。
4 讨论
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NOG小鼠为重度免疫缺陷小鼠,体内无成熟T细胞、B细胞和功能性NK细胞,对人源细胞和组织免疫排斥反应低,是人源免疫细胞毒性评价的理想动物模型[10]。研究结果提示,给予MAK细胞后NOG小鼠临床症状未见明显异常,注射部位未见明显刺激反应,同时动物体质量增长和摄食情况未见明显异常。从血液学指标看,由于MAK细胞属于淋巴细胞,体外的输注很可能会引起动物血液中LYMP%升高,同时导致BASO%降低,因此LYMP%统计学意义的升高、BASO%统计学意义的降低可能与输入了较多数量MAK细胞或者细胞在体内增殖相关,结合组织病理学检查结果,高剂量组动物出现多脏器混合细胞聚集(MAK细胞、单核巨噬细胞、粒细胞等),认为血液学指标的改变与给予MAK细胞具有相关性。本研究给予MAK细胞可见小鼠血清IFN-γ 水平显著升高,且血清IFN-γ水平与MAK细胞体内存续相关。细胞因子是细胞治疗产品发挥药效作用的重要机制之一[11],提示IFN-γ水平升高与MAK 细胞发挥药效作用相关。应用免疫缺陷动物对细胞治疗产品进行安全性评价,可能无法充分评价细胞产品引起细胞因子风暴风险,临床应用时需注意炎性细胞因子监测[12-13]。组织病理学结果提示给予MAK细胞后,组织脏器出现免疫细胞的聚集,提示MAK细胞激活动物免疫应答反应。研究报道,嵌合抗原受体T细胞等细胞产品可能导致神经毒性综合征不良反应[14],MAK 细胞小鼠临床前毒性评价中未见相关神经系统病变。
对细胞治疗产品而言,药代动力学研究(或称生物分布研究)旨在评估细胞在体内的分布、迁移和消除特性,细胞治疗产品的分布及存续时间是影响细胞治疗产品有效性和安全性的重要因素[15]。本研究在毒性评价基础上,伴随生物分布研究,考察了MAK细胞在外周血中动态变化及在组织脏器中分布和消除行为[16]。流式方法检测外周血中MAK细胞含量结果提示,末次给药结束后28 d,高剂量组动物血液中仍可检测到一定数量MAK细胞,qPCR方法检测组织中MAK细胞基因含量结果提示,末次给药结束时MAK细胞集中分布在肝脏、脾脏、肾脏等血流丰富脏器,末次给药结束后28 d,多数组织脏器均可检测到MAK基因,且基因拷贝数显著增加,提示随着给药后时间的延长MAK细胞在动物体内出现明显增殖,这也解释了末次给药结束后28 d各组织脏器出现更加显著的混合细胞聚集现象。此次伴随生物分布研究未检测到MAK细胞消除情况,考虑在后续试验中延长观测期,以充分揭示MAK细胞在组织脏器的分布、消除规律。
综上所述,本研究使用免疫缺陷小鼠较全面地评估了MAK细胞的体内潜在毒性风险及分布特征。研究结果提示,MAK细胞可在免疫缺陷小鼠体内增殖,未见明显毒性风险。本研究数据可支持其临床试验注册申请,为相关产品开展非临床安全性研究提供借鉴。
基金
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  • 国家重点研发计划课题资助(2021YFA1101602)
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2024年第59卷第20期
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doi: 10.11669/cpj.2024.20.001
  • 接收时间：2024-06-25
  • 首发时间：2025-12-30
  • 出版时间：2024-10-22
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  • 收稿日期：2024-06-25
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国家重点研发计划课题资助(2021YFA1101602)
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    1 中国食品药品检定研究院安全评价研究所, 药物非临床安全评价研究北京市重点实验室, 北京 100176
    2 吉林省拓华生物科技有限公司, 吉林 四平 136001

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* 周晓冰,女,博士,研究员 研究方向:药物毒理学研究 Tel:(010)67872233-8203
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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