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

为了阐明影响人体造血细胞在裸鼠体内移植的因素，我们比较了免疫系统附加遗传缺陷的裸鼠淋巴样肿瘤的可移植性。根据褐黄色基因和x连锁免疫缺陷（xid）基因的表达将裸鼠分为：1)高NK裸鼠（C57BL/6N nu/nu）， 2)低NK裸鼠（C57BL/ 6bg /bg nu/nu）， 3)高NK裸鼠（CBA/N nu/nu）， 4)低NK裸鼠（NIH(S)III） B细胞缺陷。含xid裸小鼠（CBA/N和NIH(S) III裸小鼠）对T细胞淋巴瘤和B细胞淋巴瘤的反应较不含xid裸小鼠（B6和米色裸小鼠）好。此外，在xid表达的裸鼠中，CBA/N背景的裸鼠比NIH(S)背景的裸鼠的反应稍好。xid表达的（CBA/N × C57BL/6N）F_1雄性裸鼠的异种移植率高于未表达xid的（C57BL/66 × CBA/N）F_1雄性裸鼠，但未达到与CBA/N裸鼠相同的水平。另一方面，在有限的实验条件下（接种100x10^5 T细胞淋巴瘤），在裸鼠中引入米色基因，尽管NK活性降低，但人类肿瘤异种移植物的存活率最低。虽然移植了人淋巴瘤的裸鼠能够产生针对人肿瘤的抗体，但在CBA/N裸鼠血清中没有或很少观察到针对异种移植物的抗体。此外，NK细胞利用抗体依赖性细胞毒性（antibody dependent cellular cytotoxicity， ADCC）介导了人淋巴样肿瘤异种移植物的排斥反应。本报告的结果证实了xid对人肿瘤异种移植裸鼠的影响，提示血清IgM中可能存在抗体介导ADCC对异种造血细胞的排斥反应。

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.