Intestinal allograft tolerance in large animals

项目摘要：尽管最近免疫抑制的改善，小肠移植物/患者的存活率 然而，ITx移植仍然是次优的，限制了这种疗法的更广泛应用。诱导供体- 需要对任何器官的特异性耐受性以消除与免疫抑制相关的共病 治疗诱导耐受性对于ITx是特别期望的，这是由于：（1）需要高水平的 免疫抑制，以防止小肠移植排斥反应;（2）并发症与重型 免疫抑制;（3）受体平均年龄小。然而，据我们所知， 肠同种异体移植物尚未在临床前模型中得到广泛研究。即使在啮齿动物模型中， 有报道显示对小肠的耐受性，但一种成功的策略是通过诱导 持久的混合异基因嵌合体。该提案的总体目标是开发一种大型动物临床前 ITx后耐受性诱导的模型，并开发适合于亲本中耐受性诱导的方案 至儿童（活体供者LD）ITx。我们最近报道，排斥率似乎是较高的临床受体 与包括供体肝脏的多脏器移植（MVTx）相比， 胃和胰腺值得注意的是，我们第一次发现，T细胞混合嵌合体， 在iITx后，甚至更常见的是在MVTx后，没有GVHD，与排斥反应减少有关 rates.我们假设在这些MVTx接受者中存在移植物抗宿主反应（GVHR）克隆， 促进移植物内所含供体祖细胞的植入，并进一步假设， 在GVHR期间移植额外的造血干细胞（HSC）将增加 即使在iITx接受者中也存在嵌合体和耐受诱导。从移植物迁移到移植物的早期GVHR 接受者的外周免疫系统（淋巴造血GVH应答，或LGVHR）使造血干细胞（造血干细胞） 这些造血祖细胞植入的“空间”。在这个建议中，我们将利用MHC近交系 小型猪，唯一允许具有确定的GVH的可重复移植的大型动物模型， 宿主-移植物（HvG）遗传屏障，以解决上述假设并制定临床相关的LD ITx 耐受诱导模型我们将首先建立原位iITx和MvTx的猪模型， 研究机构的临床方案，并确定GVH和HvG同种异体反应性在驱动嵌合体中的作用， 临床结果（目标1）。然后，我们将利用LGVHR和供体HSC来实现长期耐受。 目的1（Aim 2）中的模型中的同种异体移植物受体。该提案中的研究可能最终具有临床意义。 适用性，可以解决ITx中最有问题的问题，并大大改善这一结果。 治疗方式

Project Abstract: Despite recent improvements in immunosuppression, graft/patient survival of small intestinal transplantation (ITx) remains suboptimal, limiting the broader application of this therapy. Induction of donor- specific tolerance to any organ is desirable to eliminate co-morbidities associated with immunosuppressive treatment. The induction of tolerance is particularly desirable for ITx due to: (1) the requirement for high levels of immunosuppression to prevent rejection of small bowel grafts; (2) complications associated with heavy immunosuppression; and (3) the young average age of the recipients. However, to our knowledge, tolerance of intestinal allografts has not been extensively studied in preclinical models. Even in rodent models, there are few reports demonstrating tolerance to small intestine, but one successful strategy has been through the induction of durable mixed allogeneic chimerism. The overall goal of this proposal is to develop a large animal preclinical model for tolerance induction following ITx and to develop a protocol appropriate for tolerance induction in parent to child (living donor LD) ITx. We recently reported that rejection rates appear to be higher in clinical recipients of isolated intestinal transplants (iITx) compared to multivisceral transplants (MVTx), which include donor liver, stomach and pancreas. Notably we have found, for the first time, that T cell mixed chimerism which develops without GVHD following iITx and even more commonly following MVTx, is associated with reduced rejection rates. We hypothesize that the presence of graft-vs-host-reactive (GVHR) clones in these MVTx recipients facilitates engraftment of donor progenitor cells contained within the grafts, and further hypothesize that transplantation of additional hematopoietic stem cells (HSCs) during this period of the GVHR will augment chimerism and tolerance induction even in iITx recipients. The early GVHR that migrates from the graft to the recipient’s peripheral immune system (lymphohematopoietic GVH response, or LGVHR) makes hematopoietic “space” for engraftment of these hematopoietic progenitors. In this proposal, we will utilize MHC inbred miniature swine, the only large animal model that allows reproducible transplantation with defined GVH and host-vs-graft (HvG) genetic barriers, to address the above hypotheses and develop a clinically relevant LD ITx tolerance induction model. We will first establish a porcine model of orthotopic iITx and MvTx that parallels our institution’s clinical protocol and determine the role of GVH and HvG alloreactivity in driving chimerism and clinical outcomes (Aim 1). We will then utilize the LGVHR and donor HSCs to achieve tolerance in long-term allograft acceptors in the models in Aim 1 (Aim 2). The studies in this proposal may have eventual clinical applicability that could solve the most problematic issues in ITx and vastly improve the outcomes of this therapeutic modality.