Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202-1760, USA.
Transplantation. 2012 Mar 15;93(5):469-76. doi: 10.1097/TP.0b013e318242bddf.
Mixed chimerism is an effective approach for tolerance induction in transplantation. Strategies to achieve mixed chimerism with relatively low toxicity have significantly expanded the clinical use of chimerism.
Allogeneic bone marrow transplants were performed between B6 (H2(b)) and BALB/c (H2(d)) mice. Recipient B6 mice were nonmyeloablatively conditioned with anti-αβ-T-cell receptor, anti-CD154, or rapamycin alone or in different combinations. A total of 15 × 10(6) BALB/c bone marrow cells were transplanted after varying doses of cGy of total body irradiation.
Pretreatment of recipients with anti-CD154 and rapamycin with or without T-cell lymphodepletion reduced the total body irradiation requirement to 100 cGy for establishing stable mixed chimerism. The mixed chimeras accepted donor islet allografts long term. Lymphocytes from mixed chimeras did not respond to host or donor antigens, yet were reactive to major histocompatibility complex-disparate third-party alloantigens, demonstrating functional donor-specific T-cell tolerance. No antibodies against donor and host were detected in mixed chimeras, suggesting humoral tolerance. Mixed chimeras showed no cytotoxicity to donor cells, but a similar rapid killing rate for major histocompatibility complex disparate third-party B10.BR cells compared with T-cell-deficient and wild-type controls in in vivo cytotoxicity assays, suggesting donor-specific tolerance in the innate immune cells was achieved in mixed chimeras.
Mixed chimeras prepared with low-intensity nonmyeloablative conditioning exhibit systemic tolerance in innate immunity and tolerance in adaptive T- and B-cell immune responses.
嵌合体是移植中诱导耐受的有效方法。采用毒性相对较低的策略来实现嵌合体，显著扩大了嵌合体的临床应用。
B6（H2（b））和 BALB/c（H2（d））小鼠之间进行异基因骨髓移植。受者 B6 小鼠用抗-αβ-T 细胞受体、抗-CD154 或雷帕霉素单独或不同组合进行非清髓预处理。在不同剂量的全身照射（cGy）后，共移植 15×10（6）个 BALB/c 骨髓细胞。
用抗-CD154 和雷帕霉素预处理受者，或联合 T 细胞耗竭，可将建立稳定嵌合体所需的全身照射剂量降低至 100 cGy。混合嵌合体长期接受供体胰岛同种异体移植物。混合嵌合体的淋巴细胞对宿主或供体抗原无反应，但对主要组织相容性复合物不同的第三方同种异体抗原有反应，表明具有功能性供体特异性 T 细胞耐受。混合嵌合体中未检测到针对供体和宿主的抗体，提示存在体液耐受。混合嵌合体对供体细胞无细胞毒性，但在体内细胞毒性试验中，对主要组织相容性复合物不同的第三方 B10.BR 细胞的杀伤速度与 T 细胞缺陷和野生型对照相似，表明在混合嵌合体中实现了固有免疫细胞中的供体特异性耐受。
用低强度非清髓预处理制备的混合嵌合体在固有免疫中表现出全身性耐受，在适应性 T 和 B 细胞免疫反应中表现出耐受。
