异种移植中抗体介导的排斥反应:它能被预防或逆转吗?

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
ACS Applied Electronic Materials Pub Date : 2023-07-01 Epub Date: 2023-08-07 DOI:10.1111/xen.12816
Zahra Habibabady, Gannon McGrath, Kohei Kinoshita, Akihiro Maenaka, Ileka Ikechukwu, Gabriela F Elias, Tjasa Zaletel, Ivy Rosales, Hidetaka Hara, Richard N Pierson, David K C Cooper
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引用次数: 0

摘要

抗体介导的排斥反应(AMR)是猪移植物移植到免疫抑制的非人类灵长类动物(NHP)后失败的最常见原因。与急性细胞排斥反应相比,同种异体移植中AMR的发生率(46%对7%)远高于同种异体移植(3%对63%)。尽管同种异体移植物中的AMR通常可以逆转,但据我们所知,还没有在猪异种移植物中成功逆转的报道。由于在异种移植模型中预防或逆转AMR的经验较少,对同种异体移植物患者的研究结果提供了更多信息。这些包括(i)血清抗供体抗体的耗竭或中和,(ii)补体激活的抑制,(iii)靶向B细胞或浆细胞的治疗,以及(iv)抗炎治疗。例如,通过血浆置换来消耗或中和抗猪抗体,可以有效地消耗抗体,但它们会在几天内恢复。IgG降解酶不会耗尽IgM。尽管人补体调节蛋白在猪移植物上表达,但抑制系统补体激活可能是必要的,特别是如果要逆转AMR。潜在的治疗方法包括(i)抑制补体激活(例如,通过IVIg、C1-INH或抗C5抗体),但一些补体抑制剂对NHP无效,例如eculizumab。可能的B细胞靶向治疗包括(i)B细胞耗竭,(ii)浆细胞耗竭,,(iii)调节B细胞活化,和(iv)增强调节性B和/或T细胞的产生。在抗炎药中,抗IL6R单克隆抗体和TNF阻断剂越来越多地在异种移植模型中进行测试,但没有确切证据表明它们可以逆转AMR。应将越来越多的注意力集中在测试上述疗法的组合上。我们认为,全身补体抑制剂的治疗可能是最有效的,可能与抗炎药联合使用(如果尚未使用)。最终,可能需要对器官源猪进行进一步的基因工程以完全解决该问题,例如,敲除或敲除SLA,和/或表达PD-L1、HLA E和/或HLA-G。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?

Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti-donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti-inflammatory therapy. Depletion or neutralization of anti-pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG-degrading enzymes do not deplete IgM. Despite the expression of human complement-regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti-C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell-targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti-inflammatory agents, anti-IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti-inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ-source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD-L1, HLA E, and/or HLA-G.

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CiteScore
7.20
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4.30%
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