Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, n = 7) or with modified SLA expression (treatment group, n = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding β2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA–down-regulated lung transplants in the absence of immunosuppression.

中文翻译：

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猪肺移植物中猪白细胞抗原表达的敲低使移植物无需免疫抑制即可存活


免疫排斥仍然是同种异体肺移植长期存活的主要障碍。主要组织相容性复合物分子和次要组织相容性抗原的表达会触发同种异体免疫反应，从而导致同种异体移植物排斥。因此，移植结果取决于长期免疫抑制，这会带来严重的副作用。为了解决这个问题，我们研究了永久下调猪白细胞抗原（SLA）表达的基因工程移植物在猪同种异体肺移植（LTx）模型中预防排斥反应的效果。 SLA 表达未修饰的小型猪供体肺（对照组， n = 7) 或使用修改后的 SLA 表达（治疗组， n = 7) 用于评估 SLA 敲低对同种异体移植物存活的影响以及对 LTx 后终止最初 4 周免疫抑制期后免疫反应的性质和强度的影响。下调 SLA 表达的基因工程是在离体肺灌注过程中通过慢病毒转导靶向编码 β2-微球蛋白和 II 类反式激活蛋白的 mRNA 的短发夹 RNA 来实现的。对照组的所有移植物在 3 个月内均被排斥，而治疗组的 7 只动物中有 5 只在 2 年监测期间在没有免疫抑制的情况下保持了移植物存活。与对照组相比，SLA 沉默的肺受体的血清中供体特异性抗体和促炎细胞因子浓度较低。总之，这些数据证明了在没有免疫抑制的情况下 SLA 下调肺移植的生存益处。