Bringing Clarity to the Murky Problem of Cardiac Allograft Vasculopathy.
Bringing Clarity to the Murky Problem of Cardiac Allograft Vasculopathy.
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澄清心脏同种异体移植血管病的模糊问题。
DOI：
10.1016/j.ajpath.2022.05.002
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Gill,RonaldG
中科院分区：
文献类型：
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作者：
Gill,RonaldG
尽管大多数已发表的涉及心脏同种异体移植排斥反应的临床前小鼠模型的研究倾向于集中在急性排斥反应和耐受诱导的问题上，但可以说，临床移植领域更迫切的需求是更好地了解慢性同种异体移植物损伤。也就是说，慢性移植物损伤是一个比急性排斥反应导致的早期移植物丢失更严重的临床问题。在心脏移植中，心脏同种异体移植物血管病变（CAV）是一种明显的冠状动脉疾病，在移植1后随时间推移发生，并且仍然是移植损失和受体死亡的主要来源。2，3此外，在过去几年中，供体特异性抗体（DSA）的产生与CAV和慢性同种异体移植排斥反应（通常通过抗体介导的排斥反应（AMR）过程）密切相关，这一点变得越来越明显。4，5更重要的是，一旦DSA生成并发生CAV，可用于防止最终同种异体移植物失败的治疗选择有限。因此，除了推进临床急性和慢性同种异体移植排斥反应的研究外，还必须开发临床前动物模型，以更好地了解CAV的发病机制。确定合适的CAV小鼠模型，特别是涉及AMR的模型，一直具有挑战性，因为有用的小鼠模型需要避免原发性急性排斥反应，但又允许产生长期慢性同种异体移植物损伤。用于产生CAV的早期小鼠模型在供体和受体之间采用有限的抗原差异，例如对雌性受体中的次要雄性HY抗原的反应6或对在单个主要组织相容性复合体II类分子上与宿主不同的供体的反应。7 e9然而，这些模型倾向于在很大程度上引起细胞形式的慢性排斥，而不是清楚地反映DSA相关的CAV。在小鼠中发展CAV的另一种方法是通过用瞬时或次优免疫调节剂治疗受体，这导致慢性而不是急性排斥反应，尽管DSA在这些模型中的作用不太明确。9 e11最近评估DSA在触发CAV中的作用的方法是通过将供体主要组织相容性复合物I类特异性抗体直接转移到携带心脏同种异体移植物的免疫缺陷受体。12，13虽然这些不同的方法已被证明可用于研究小鼠中CAV的某些方面，但仍然需要开发DSA相关CAV的改进动物模型。
Although most published studies involving preclinical mouse models of cardiac allograft rejection tend to center on the issues of acute rejection and tolerance induction, arguably the more pressing need in the field of clinical transplantation is better understanding of chronic allograft injury. That is, chronic graft injury is a far greater current clinical problem than is early graft loss due to acute rejection. In heart transplantation, cardiac allograft vasculopathy (CAV) is a form of pronounced coronary artery disease that occurs over time after transplant 1 and remains the major source of transplant loss and recipient mortality. 2, 3 Moreover, it has become increasingly apparent over the past several years that the development of donor-specific antibodies (DSAs) is strongly associated with CAV and chronic allograft rejection in general through the process of antibody-mediated rejection (AMR). 4, 5 More importantly, once DSA is generated and CAV occurs, limited treatment options are available for preventing eventual allograft failure. As such, in addition to advancing the study of clinical acute and chronic allograft rejection, it is imperative to develop preclinical animal models that permit greater mechanistic insights into the pathogenesis of CAV. Identifying suitable mouse models of CAV, especially involving AMR, has been challenging because useful mouse models need to avoid primary acute rejection and yet be permissive for generating longer-term chronic allograft injury. Early mouse models used to generate CAV employed limited antigen disparity between donor and recipient, such as responses to the minor male HY antigen in female recipients 6 or to donors that differ from the host at a single major histocompatibility complex class II molecule. 7 e9 However, these models tended to largely invoke a cellular form of chronic rejection rather than clearly reflect DSA-associated CAV. Another means of developing CAV in mice is through the treatment of recipients with transient or suboptimal immunemodifying agents, which results in chronic rather than acute rejection, although the role of DSA in these models is less defined. 9 e11 A more recent approach to assess the role of DSA in triggering CAV is through the direct transfer of antibodies specific for donor major histocompatibility complex class I to immune-deficient recipients bearing a cardiac allograft. 12, 13 While these varied approaches have proven useful for studying some aspects of CAV in mice, there remains an onging need to develop improved animal models of DSA-associated CAV.