Major xenoantigens for neovascularised porcine xenografts: the role of PERV and MHC in rejection and tolerance

使用供体猪血管的猪器官跨物种移植（异种移植）被识别猪血管上特殊靶点（异种抗原）的抗体排斥；其他使用受体（不是供体猪）血管的猪组织移植（细胞移植）会被称为CD4 T细胞的白细胞排斥。被异反应性CD4 T细胞识别的猪靶标是未知的。我们计划确定参与细胞异种移植排斥反应的主要靶点。然后，这些信息可以用来特异性地移除或禁用那些能够识别猪组织的CD4 T细胞，从而促进异种移植物的存活或耐受，而不会产生免疫抑制。通过这种方式，剩余的CD4 T细胞群和免疫系统得以完整保存。最近的研究表明，猪病毒（PERV）可以从猪组织异种移植物传播到受体组织。我们的研究还表明，异种移植排斥过程与感染猪病毒的移植受体细胞的免疫识别密切相关。我们计划调查这种关系，并确定猪组织异种移植物的免疫破坏是否主要是由于对其携带的猪病毒产生的免疫反应。作为这一概念的延伸，我们将研究长期的异种移植物存活（耐受性）是否与缺乏对猪病毒的免疫反应性有关，从而是否与猪病毒持续传播到宿主组织的能力有关。这一结果可能导致移植患者出现不想要的疾病。为了防止这些问题，我们的研究将确定在移植前是否有必要将这种猪病毒从供体猪组织中消除，例如通过开发强效抗病毒药物和或通过开发经过基因工程改造的猪群来减少猪病毒（PERV）。

Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants (cellular transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major target(s) involved in cellular xenograft rejection. This information can then be used to specifically remove or disable only those CD4 T cells capable of recognising the pig tissue and hence facilitate xenograft survival or tolerance without immunosuppression. In this way, the remainder of the CD4 T cell population and immune system is preserved intact. Recent studies have demonstrated that a pig virus (PERV) can be transmitted from pig tissue xenografts to recipient tissues. Our studies have also suggested that the process of xenograft rejection and the immunological recognition of transplant recipient cells infected with the pig virus, are closely related. We plan to investigate this relationship and ascertain whether the immunological destruction of the pig tissue xenograft is largely due to an immune response generated against the pig virus(es) it carries. As an extension of this concept, we will investigate whether long-term xenograft survival (tolerance) is associated with lack of immune reactivity to the pig virus and hence a continual capacity for pig virus to be transmitted to host tissues. This outcome could result in the development of unwanted disease(s) in transplant patients. To prevent these problems, our studies will determine whether it will be essential for such pig virus to be eliminated from the donor pig tissue before transplantation, e.g. by the development of potent anti-viral agents and-or via the development of pig herds that have been genetically engineered to be pig virus (PERV)-deficient.