Ji P, Xia G, Sefrioui H, Rutgeerts O, Segers C, Waer M
Laboratory for Experimental Transplantation, University of Leuven, Belgium.
Transplantation. 1999 Jul 15;68(1):130-6. doi: 10.1097/00007890-199907150-00024.
We have previously demonstrated that in a concordant hamster-to-nude rat cardiac transplant model, T-independent specific B-lymphocyte and natural killer (NK)-cell tolerance could be induced, leading to long-term xenograft (Xg) survival. Here, we investigated whether the same could be achieved in a clinically more relevant semi-discordant model involving hamster hearts transplanted into pre-sensitized, nude rats.
Sensitized, nude rats with high titers of anti-hamster immunoglobulin (Ig)M xenoantibodies (XAbs) were prepared by transplanting a first hamster heart without treatment. One week after rejection, a complete tolerizing regimen was given, including the following: a) an i.v. injection of hamster heart antigens; b) a 4-week administration of malononitriloamide; and c) a single injection of an anti-NK antiserum. Two weeks later, a second hamster heart was grafted. The isotype and level of XAb were examined by fluorescence-activated cell sorting. NK cytotoxicity was evaluated by a standard 4-hr 51Cr release assay. Hamster heart Xgs were examined by conventional histologic and immunohistochemical analysis.
Untreated, presensitized, nude rats developing high titers of IgM XAb underwent hyperacute rejection within 4 hr (n=4) after transplantation of the second hamster heart. Immunohistochemical analysis showed intensive staining for IgM and C3 along the vascular endothelia in the rejected Xgs. In contrast, presensitized, nude rats receiving the complete tolerizing regimen had a rapid decrease in anti-hamster IgM XAb. The second hamster hearts were not rejected and showed long-term survival even after withdrawal of malononitriloamide (n=6). Moreover, tolerant rats showed specific B-lymphocyte tolerance and a specific continuous absence of anti-hamster NK-cell reactivity.
T-independent B-lymphocyte and NK-cell xenotolerance can also be achieved in recipients with pre-existing IgM XAb.
我们之前已经证明，在仓鼠到裸鼠的心脏移植匹配模型中，可以诱导非T细胞依赖性特异性B淋巴细胞和自然杀伤（NK）细胞耐受，从而实现长期异种移植（Xg）存活。在此，我们研究了在临床上更具相关性的半不匹配模型（将仓鼠心脏移植到预先致敏的裸鼠体内）中是否也能实现同样的结果。
通过移植未经处理的第一颗仓鼠心脏，制备出具有高滴度抗仓鼠免疫球蛋白（Ig）M异种抗体（XAbs）的致敏裸鼠。在排斥反应发生一周后，给予完整的耐受诱导方案，包括：a）静脉注射仓鼠心脏抗原；b）持续4周给予丙二腈酰胺；c）单次注射抗NK抗血清。两周后，移植第二颗仓鼠心脏。通过荧光激活细胞分选检测XAb的同种型和水平。通过标准的4小时51Cr释放试验评估NK细胞毒性。通过常规组织学和免疫组织化学分析检查仓鼠心脏异种移植。
未接受处理的预先致敏裸鼠在产生高滴度IgM XAb后，在移植第二颗仓鼠心脏后4小时内发生超急性排斥反应（n = 4）。免疫组织化学分析显示，在被排斥的异种移植中，血管内皮上IgM和C3染色强烈。相比之下，接受完整耐受诱导方案的预先致敏裸鼠抗仓鼠IgM XAb迅速减少。第二颗仓鼠心脏未被排斥，即使在停用丙二腈酰胺后仍显示长期存活（n = 6）。此外，耐受的大鼠表现出特异性B淋巴细胞耐受以及抗仓鼠NK细胞反应性的特异性持续缺失。
在预先存在IgM XAb的受体中也可以实现非T细胞依赖性B淋巴细胞和NK细胞异种耐受。
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