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Combination of CTLA4-FasL gene transfer and allogeneic bone marrow transplantation led to durable macrochimerism and donor-specific tolerance in mouse model

机译:CTLA4-FasL基因转移与同种异体骨髓移植相结合导致小鼠模型中持久的大嵌合和供体特异性耐受

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Mixed hemopoietic chimerism is capable of inducing donor specific tolerance, thus eliminating the chronic immunosuppressive therapy following organ transplantation. As yet no safe and effective tolerance protocol is available for clinical implementation. Here we describe an alternative nonmyeloablative based strategy of using a single injection of recombination adenovirus vector encoding CTLA4-FasL fusing gene and donor bone marrow cells to promote durable mixed macrochiinerism (>20 percent on 140 d). Chimeras exhibited robust donor-specific tolerance, as evidenced by acceptance of felly allogeneic skin grafts (the mean survival time (MST)>200 d) and rejection of third-party skin grafts in a normal manner (MST<10 d). In model, the frequencies of helper T lymphocyte precursor (BTLp) cytotoxic T lymphocyte precursor (CTLp) were greatly reduced on day 14 after transplantation, suggesting that CTLA4-FasL led to rapid systemic peripheral tolerance to facilitate the bone marrow engraftment, while both HTLp and CTLp remained at low level only in recipient mice with chimerism on day 140 after transplantation, demonstrating that long-term skin grafts tolerance was associated with stable mixed chimerism, central deletion of donor specific T cell may be the main mechanism for tolerance maintenance.
机译:混合造血嵌合体能够诱导供体特异性耐受,从而消除器官移植后的慢性免疫抑制治疗。迄今为止,尚无安全有效的耐受方案可用于临床。在这里,我们描述了一种替代的基于非清髓性的策略,该策略使用单次注射的重组腺病毒载体编码CTLA4-FasL融合基因和供体骨髓细胞的重组腺病毒载体,以促进持久的混合巨细胞增多症(在140天时> 20%)。嵌合体表现出强大的供体特异性耐受性,如接受绒毛状同种异体皮肤移植物(平均存活时间(MST)> 200 d)和以正常方式拒绝第三方皮肤移植物(MST <10 d)所证明。在模型中,在移植后第14天,辅助T淋巴细胞前体(BTLp)细胞毒性T淋巴细胞前体(CTLp)的频率大大降低,这表明CTLA4-FasL导致快速的全身性外周耐受以促进骨髓植入,而两个HTLp CTLp和CTLp仅在移植后第140天在具有嵌合体的受体小鼠中保持在低水平,表明长期的皮肤移植耐受性与稳定的混合嵌合体有关,供体特异性T细胞的中央缺失可能是维持耐受性的主要机制。

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