Clinical lung xenotransplantation--what donor genetic modifications may be necessary?
Clinical lung xenotransplantation--what donor genetic modifications may be necessary?
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DOI：
10.1111/j.1399-3089.2012.00708.x
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发表时间：
2012-05
影响因子：
3.9
通讯作者：
Pierson RN 3rd
中科院分区：
文献类型：
--
作者：
Cooper DK;Ekser B;Burlak C;Ezzelarab M;Hara H;Paris L;Tector AJ;Phelps C;Azimzadeh AM;Ayares D;Robson SC;Pierson RN 3rd
异种肺移植成功的障碍似乎比其他器官更大。这一困难可能与几个宏观解剖因素有关，如独特脆弱的肺实质和相关的血液供应，导致移植物功能对血管完整性丧失(也适用于同种异体移植物)引起的节段性或肺叶气道泛滥的易感性增加。也有微观解剖学方面的考虑，例如存在大量的常驻炎症细胞，如肺血管内巨噬细胞和自然杀伤(NK)T细胞，以及与微血管系统相关的高水平的von Willebrand因子(VWF)。我们已经考虑了使临床异种肺移植成功所必需的发展。我们认为，这只能通过对器官来源的猪进行多重基因改造来实现，特别是使血管系统对血栓具有抵抗力。需要克服的主要问题是多方面的，包括(1)天然免疫反应(抗体、补体、供体肺和受体巨噬细胞、单核细胞、中性粒细胞和NK细胞)；(2)获得性免疫反应(T和B细胞)；(3)凝血功能失调；(4)炎症反应(如肿瘤坏死因子α、IL 6、HMGB1、C反应蛋白)。我们认为，仅提供正常的血栓调节所需的基因操作可能包括导入人血栓调节蛋白/内皮蛋白C受体、和/或组织因子途径抑制物、和/或CD39/CD73的基因；猪vWF的问题也可能需要解决。如果异种肺移植要取得成功，似乎需要探索每一种可用的治疗途径。要启动异种肺移植的临床试验，即使是作为通向同种异体移植的桥梁(具有足够长的存活时间以获得人类同种异体肺移植的现实可能性)，还需要取得重大进展和大量的实验工作。然而，随着猪基因工程技术的稳步发展，我们乐观地认为，在可预见的未来，成功的临床异种肺移植的目标是可以实现的。乐观的观点是，如果实验性的猪肺异种移植能够成功处理，这种异种移植和所有其他形式的异种移植的临床应用很可能变得更加可行。
Barriers to successful lung xenotransplantation appear to be even greater than for other organs. This difficulty may be related to several macro anatomic factors, such as the uniquely fragile lung parenchyma and associated blood supply that results in heightened vulnerability of graft function to segmental or lobar airway flooding caused by loss of vascular integrity (also applicable to allotransplants). There are also micro-anatomic considerations, such as the presence of large numbers of resident inflammatory cells, such as pulmonary intravascular macrophages and natural killer (NK) T cells, and the high levels of von Willebrand factor (vWF) associated with the microvasculature. We have considered what developments would be necessary to allow successful clinical lung xenotransplantation. We suggest this will only be achieved by multiple genetic modifications of the organ-source pig, in particular to render the vasculature resistant to thrombosis. The major problems that require to be overcome are multiple and include (i) the innate immune response (antibody, complement, donor pulmonary and recipient macrophages, monocytes, neutrophils, and NK cells), (ii) the adaptive immune response (T and B cells), (iii) coagulation dysregulation, and (iv) an inflammatory response (e.g., TNF-α, IL-6, HMGB1, C-reactive protein). We propose that the genetic manipulation required to provide normal thromboregulation alone may include the introduction of genes for human thrombomodulin/endothelial protein C-receptor, and/or tissue factor pathway inhibitor, and/or CD39/CD73; the problem of pig vWF may also need to be addressed. It would appear that exploration of every available therapeutic path will be required if lung xenotransplantation is to be successful. To initiate a clinical trial of lung xenotransplantation, even as a bridge to allotransplantation (with a realistic possibility of survival long enough for a human lung allograft to be obtained), significant advances and much experimental work will be required. Nevertheless, with the steadily increasing developments in techniques of genetic engineering of pigs, we are optimistic that the goal of successful clinical lung xenotransplantation can be achieved within the foreseeable future. The optimistic view would be that if experimental pig lung xenotransplantation could be successfully managed, it is likely that clinical application of this and all other forms of xenotransplantation would become more feasible.
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影响因子：
4.4
作者：
Baumann, BC;Forte, P;Seebach, JD
通讯作者：
Seebach, JD
影响因子：
3.9
作者：
Bush, Errol L.;Barbas, Andrew S.;Lin, Shu S.
通讯作者：
Lin, Shu S.
DOI：
10.1152/ajplung.1999.276.1.l146
发表时间：
1999-01-01
影响因子：
4.9
作者：
Brain, JD;Molina, RM;Warner, AE
通讯作者：
Warner, AE
影响因子：
3.9
作者：
Burlak, Christopher;Wang, Zheng-Yu;Tector, A. Joseph
通讯作者：
Tector, A. Joseph
影响因子：
56.9
作者：
Brummelkamp, TR;Bernards, R;Agami, R
通讯作者：
Agami, R