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Analysis of reiection mechanism of human hematopoietic cell xenotransplantation in immunodeficiency mice

免疫缺陷小鼠人造血细胞异种移植的排斥机制分析

基本信息

批准号：
03680043
负责人：
SHIMAMURA Kazuo
金额：
$ 1.28万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

In order to elucidate the factors influencing the takes human hematopoietic cells in nude mice, we compared the transplantability of lymphoid neoplasm in nude mice with additional genetic defects in the immune system. The nude mice strains tested were classified as follows by expression of the beige gene and x-linked immunodeficiency (xid) gene : 1) high NK nude (C57BL/6N nu/nu), 2) low NK nude (C57BL/6 bg/bg nu/nu), 3) high NK nude with B cell defect (CBA/N nu/nu), and 4) low NK nude with B cell defect (NIH(S)III). Takes of human xenografts including T cell lymphoma and B cell lymphoma were better in nude mice with xid (CBA/N and NIH(S) III nude mice) then in nude mice without xid (B6 and beige nude mice). In addition, among the nude mice with xid expression, the takes were slightly better in nude mice with a CBA/N background than in those with a NIH(S) background. Moreover, the xenotransplantation rate in (CBA/N x C57BL/6N)F_1 male nude mice with xid expression was higher than in (C57BL/66 x CBA/N)F_1 males without xid expression but did not reach same level as that in CBA/N nude. On the other hand, introduction of the beige gene in nude mice minimally improved the takes of human tumor xenografts under limited experimental conditions ( inoculation of 100x10^5 T cell lymphoma) despite the reduction of NK activity. Although nude mice with human lymphoma xenografts were able to produce antibodies against the human tumors, no or little antibody against the xenografts was observed in CBA/N nude mice sera. In addition, rejection of human lymphoid tumor xenografts was mediated by NK cells using antibody dependent cellular cytotoxicity (ADCC). The results in present report confirmed the effect of xid on human tumor xenografts in nude mice, suggesting the existence of antibodies, possibly present in serum IgM mediating rejection of the hematopoietic cell xenografts by ADCC.

为了阐明影响人造血细胞在裸鼠体内移植的因素，我们比较了免疫系统中存在额外遗传缺陷的淋巴肿瘤在裸鼠体内的可移植性。根据米色基因和X连锁免疫缺陷(XID)基因的表达将裸鼠分为：1)高NK裸鼠(C57BL/6Nnu/nu)，2)低NK裸鼠(C57BL/6 BG/BG nu/nu)，3)高NK裸鼠伴B细胞缺陷(Cba/Nnu/nu)，4)低NK裸鼠伴B细胞缺陷(NIH(S)III)。含XID的裸鼠(CBA/N和NIH(S)Ⅲ型裸鼠)移植人T细胞淋巴瘤和B细胞淋巴瘤的能力明显好于不含XID的裸鼠(B6和米色裸鼠)。此外，在XID表达的裸鼠中，具有CBA/N背景的裸鼠的摄取略好于具有NIH(S)背景的裸鼠。XID表达的(CBA/N x C57BL/6N)F_1雄性裸鼠的异种移植成功率高于未表达XID的(C57BL/66 x CBA/N)F_1雄性裸鼠，但未达到CBA/N裸鼠的水平。另一方面，在有限的实验条件下(接种100×10~(-5)T细胞淋巴瘤)，在裸鼠体内导入米色基因可以最小限度地提高人肿瘤移植瘤的摄取率，尽管NK活性降低。CBA/N裸鼠血清中未见或仅有少量抗人淋巴瘤移植瘤的抗体产生。此外，人淋巴样肿瘤移植瘤的排斥反应是由NK细胞利用抗体依赖的细胞毒作用(ADCC)介导的。本研究结果证实XID对裸鼠人肿瘤移植瘤的作用，提示血清中可能存在抗体，可能存在于血清中，介导ADCC对造血细胞异种移植的排斥反应。