Intestinal transplantation (ITx) is the definitive treatment for intestinal failure but has the highest rejection rate among solid organ transplants, requiring high doses of immunosuppressive medication, which is associated with high rates of infection, graft-versus-host disease, and malignancy. Transplant tolerance would overcome the need for long-term immunosuppression (ISP). Using nonmyeloablative conditioning, our laboratory has developed a novel swine model of hematopoietic stem cell transplantation (HSCT) that produces durable mixed chimerism (MC) and immune tolerance without toxicity. We investigated whether durable MC would promote tolerance of subsequently transplanted donor-matched intestinal allografts without ISP. Using miniature swine with a defined major histocompatibility complex (MHC), we performed HSCT across an MHC-class-I haplotype mismatch. Immunosuppressive therapy was stopped by day 45. MC was evaluated using flow cytometry, and mixed lymphocyte reaction assays were used to evaluate cellular responses. Subsequently, orthotopic ITx was performed without ISP using a donor that was MHC-matched to the HSCT donor. The recipients were observed for 4 weeks and euthanized for tissue collection and mechanistic assays. After HSCT, the recipients developed durable multilineage MC and apparent deletional tolerance. After ITx, recipients showed no clinical or histologic signs of rejection, and chimerism was unchanged. These results demonstrate the potential value of generating durable MC to achieve transplant tolerance.

中文翻译：

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持久的混合嵌合体可能允许随后的无免疫抑制肠道移植——一项原理验证研究


肠移植 （ITx） 是肠衰竭的确定性治疗方法，但在实体器官移植中排斥反应率最高，需要高剂量的免疫抑制药物，这与高感染率、移植物抗宿主病和恶性肿瘤有关。移植耐受性将克服长期免疫抑制 （ISP） 的需求。使用非清髓性条件反射，我们的实验室开发了一种新型的造血干细胞移植 （HSCT） 猪模型，可产生持久的混合嵌合体 （MC） 和免疫耐受，而无毒性。我们研究了持久的 MC 是否会促进无 ISP 的后续移植供体匹配的同种异体肠移植物的耐受性。使用具有确定的主要组织相容性复合体 （MHC） 的微型猪，我们对 MHC I 类单倍型错配进行了 HSCT。免疫抑制治疗在第 45 天停止。使用流式细胞术评估 MC，并使用混合淋巴细胞反应测定来评估细胞反应。随后，使用与 HSCT 供体 MHC 匹配的供体在没有 ISP 的情况下进行原位 ITx。观察受体 4 周并安乐死以进行组织收集和机械测定。HSCT 后，受者出现持久的多系 MC 和明显的缺失耐受性。ITx 后，受者没有表现出排斥反应的临床或组织学体征，嵌合体没有变化。这些结果表明了生成耐用的 MC 以实现移植耐受性的潜在价值。