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Relevance of donor-specific HLA antibodies in hematopoietic cell transplantation 供体特异性 HLA 抗体与造血细胞移植的相关性
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.beha.2024.101576

Advances in hematopoietic cell transplantation have expanded the use of alternative donors such as haploidentical family donors or mismatched unrelated donors. However, donor-specific HLA antibodies (DSA) have been recognized as a significant risk factor of primary graft failure after HLA incompatible transplantation. Therefore, screening for HLA antibodies and taking DSA into consideration in the process of donor search play an increasingly important role in donor selection. If an HLA compatible donor is not available, desensitization may enable a successful transplantation. In this review, we describe the currently most widely used methods for HLA antibody detections including their pitfalls. In addition, we summarize the results of the studies on the impact of preformed DSA on transplant outcomes and their treatment options. Many more and larger studies are needed to clarify laboratory issues as well as immunological and clinical aspects in the management of DSA.

造血细胞移植的进步扩大了替代供体的使用范围,如单倍体家族供体或不匹配的非亲属供体。然而,供者特异性 HLA 抗体(DSA)已被认为是 HLA 不相容移植后导致原发性移植失败的重要风险因素。因此,在寻找供体的过程中,筛查 HLA 抗体和考虑 DSA 在供体选择中发挥着越来越重要的作用。如果无法获得 HLA 相容的供体,脱敏治疗可使移植成功。在这篇综述中,我们介绍了目前最广泛使用的 HLA 抗体检测方法,包括其误区。此外,我们还总结了有关预制 DSA 对移植结果的影响及其治疗方案的研究结果。还需要进行更多更大规模的研究,以澄清 DSA 管理中的实验室问题以及免疫学和临床方面的问题。
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引用次数: 0
From clones to immunopeptidomes: New developments in the characterization of permissive HLA-DP mismatches in hematopoietic cell transplantation 从克隆到免疫肽组:造血细胞移植中允许的 HLA-DP 错配特征研究的新进展
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.beha.2024.101575

Mismatching at the HLA-DPB1 locus occurs frequently in hematopoietic cell transplantation with unrelated donors. Despite this, HLA-DPB1 allelic mismatches have traditionally not been considered in patient-donor matching. A T-cell epitope (TCE) model for the functional assessment of permissive mismatches at this locus has nevertheless been adopted in clinical practice. While initially based on a hierarchical immunogenicity elucidated from allorecognition by T-cell clones isolated from a patient, newer developments in the understanding of this model's biological basis, including a central role for immunopeptidome divergence between mismatched allotypes, have prompted changes in the assignment of permissiveness, providing the opportunity for a more granular evaluation of graft-versus-host disease and relapse risks according to the nature and directionality of permissive mismatches. How these advances impact the assessment of permissiveness at HLA-DPB1 and potentially the intelligent selection of donors according to the main clinical goal for different patients is the subject of the present review.

在与非亲缘供体进行造血细胞移植时,经常会出现 HLA-DPB1 基因座错配的情况。尽管如此,HLA-DPB1 等位基因错配在患者与供体配型中历来不被考虑。然而,临床实践中采用了一种 T 细胞外显子(TCE)模型来对该位点的允许性错配进行功能评估。虽然该模型最初是基于从患者体内分离的 T 细胞克隆的异源识别所阐明的分级免疫原性,但人们对该模型生物学基础的认识有了新的发展,包括错配异型间免疫肽组差异的核心作用,这促使允许性的分配发生了变化,为根据允许性错配的性质和方向对移植物抗宿主疾病和复发风险进行更精细的评估提供了机会。这些进展如何影响 HLA-DPB1 的容许度评估,以及如何根据不同患者的主要临床目标智能选择供体,是本综述的主题。
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引用次数: 0
Special issue 37.3: “Genetics and function of HLA and immune-related genes in hematopoietic cell transplantation and cellular immunotherapy” 第 37.3 期特刊:"造血细胞移植和细胞免疫疗法中 HLA 和免疫相关基因的遗传与功能"。
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.beha.2024.101588
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引用次数: 0
HLA structure and function in hematopoietic-cell transplantation 造血细胞移植中的 HLA 结构和功能
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.beha.2024.101564

The degree of HLA compatibility between a patient and donor has formed the basis of donor selection since the development of allogeneic hematopoietic cell transplantation over 50 years ago and has advanced understanding of the basic immunobiology of HLA. New evidence supports a role for germline variation in the patient and the donor that do not require HLA matching for their effects to have clinical consequences. The discovery of novel non-coding polymorphisms, structural features of HLA molecules, and expression provide new models for donor selection and inspire the development of tools for clinical translation. Pairwise effects of HLA ligand/donor NK receptors may play an important role in transplant outcomes and showcase the value of understanding the role played by each constituent of the NK pathway in modulating donor responses to target antigens.

自 50 多年前异体造血细胞移植术开展以来,患者与供体之间的 HLA 相合程度一直是供体选择的基础,并加深了人们对 HLA 基本免疫生物学的理解。新的证据支持患者和供体的种系变异发挥作用,这些变异不需要 HLA 匹配就能产生临床后果。新的非编码多态性、HLA 分子的结构特征和表达的发现为供体选择提供了新的模型,并激发了临床转化工具的开发。HLA配体/供体NK受体的配对效应可能在移植结果中发挥重要作用,并显示了了解NK通路的每个组成成分在调节供体对目标抗原的反应中所起作用的价值。
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引用次数: 0
Interfering with KIR and NKG2A immune checkpoint axes to unleash NK cell immunotherapy 干扰 KIR 和 NKG2A 免疫检查点轴释放 NK 细胞免疫疗法
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-07-31 DOI: 10.1016/j.beha.2024.101568

Due to their intrinsic ability to eliminate malignant cells, natural killer (NK) cells emerge as a promising immunotherapy for cancer. While clinical studies have affirmed the safety of NK cell infusions and combination therapies have demonstrated encouraging outcomes in hematological malignancies, the efficacy of NK cell immunotherapeutic interventions remains heterogeneous across patient cohorts. Moreover, the implementation of NK cell immunotherapy in solid tumors presents notable challenges. Interfering with key NK cell inhibitory signaling pathways by targeting inhibitory killer cell immunoglobulin-like receptors (KIRs) and CD94/NK group 2 member A (NKG2A), holds promise for unleashing the full potential of NK cell-based immunotherapy. In this review, we provide an overview of the current approaches for interfering with inhibitory KIR and NKG2A signaling, exploring a selection of the multitude of combination strategies available. We discuss the significance of maintaining the delicate balance between achieving optimal suppression of NK cell inhibition and ensuring effective activation of anti-tumor effector function, while preserving the favorable safety profiles. The consideration of strategies to modulate inhibitory signaling pathways associated with KIR and NKG2A presents promising avenues for enhancing the efficacy of NK cell immunotherapy.

自然杀伤(NK)细胞具有消除恶性细胞的内在能力,因此成为一种很有前景的癌症免疫疗法。虽然临床研究证实了输注 NK 细胞的安全性,而且联合疗法在血液恶性肿瘤中也取得了令人鼓舞的结果,但 NK 细胞免疫治疗干预措施在不同患者群中的疗效仍然参差不齐。此外,在实体瘤中实施 NK 细胞免疫疗法也面临着显著的挑战。通过靶向抑制性杀伤细胞免疫球蛋白样受体(KIR)和 CD94/NK 2 组 A 成员(NKG2A)来干扰关键的 NK 细胞抑制信号通路,有望充分释放基于 NK 细胞的免疫疗法的潜力。在这篇综述中,我们概述了目前干扰抑制性 KIR 和 NKG2A 信号传导的方法,并探讨了现有的多种组合策略。我们讨论了在实现对 NK 细胞最佳抑制和确保有效激活抗肿瘤效应功能之间保持微妙平衡的重要性,同时保持良好的安全性。考虑调节与 KIR 和 NKG2A 相关的抑制信号通路的策略为提高 NK 细胞免疫疗法的疗效带来了希望。
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引用次数: 0
Cytomegalovirus in haematopoietic cell transplantation - The troll is still there 造血细胞移植中的巨细胞病毒--巨怪依然存在
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-07-26 DOI: 10.1016/j.beha.2024.101565

Patients undergoing allogeneic haematopoietic cell transplantation are prone to complications caused by viral infections. Cytomegalovirus (CMV) considerably impacts transplantation as it frequently requires antiviral intervention that evokes substantial side effects depending on the antiviral drug. Intermittent antiviral treatment may become necessary if CMV DNAemia cannot be permanently suppressed, and drug resistance may emerge that hampers and prolongs treatment. Despite sedulous endeavours, vaccination against CMV is not yet available. This review concisely summarises current approaches in managing CMV infection comprising risk factors, diagnostics including indications for resistance testing, and therapeutic options from antiviral drugs to virus-specific T cells.

接受异基因造血细胞移植的患者很容易因病毒感染而出现并发症。巨细胞病毒(CMV)对移植的影响很大,因为它经常需要抗病毒治疗,而根据抗病毒药物的不同,会产生很大的副作用。如果无法永久抑制 CMV DNA 血症,可能需要间歇性抗病毒治疗,而且可能出现耐药性,从而阻碍和延长治疗时间。尽管做了很多努力,但目前还没有针对 CMV 的疫苗。本综述简明扼要地总结了目前治疗 CMV 感染的方法,包括风险因素、诊断(包括耐药性测试的适应症)以及从抗病毒药物到病毒特异性 T 细胞的治疗方案。
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引用次数: 0
Deciphering the role of the major histocompatibility complex, the intestinal microbiome and metabolites in the pathogenesis of acute graft-versus-host disease 破译主要组织相容性复合体、肠道微生物组和代谢物在急性移植物抗宿主病发病机制中的作用
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-07-26 DOI: 10.1016/j.beha.2024.101567

Allogeneic hematologic stem cell transplantation is a cornerstone in modern hematological treatment, yet its efficacy is compromised by acute Graft-versus-Host Disease. In acute Graft-versus-Host Disease, conditioning regimen induced epithelial damage leads to release of damage and pathogen associated molecular patters which in turns triggers activation of alloreactive donor T cells, ultimately resulting in destruction of healthy tissue. Advances in major histocompatibility complex typing and preclinical studies using tissue specific major histocompatibility complex deletion have illuminated the contributions of both, hematopoietic and non-hematopoietic cells to acute Graft-versus-Host Disease pathophysiology. Concurrently, high-throughput sequencing techniques have enabled researchers to recognize the significant impact of the intestinal microbiome and newly discovered metabolites in the pathophysiology of acute Graft-versus-Host Disease. In this review, we discuss the implications of major histocompatibility complex expression on hematopoietic and non-hematopoietic cells, the effect on the intestinal microbiome and the metabolic alterations that contribute to acute Graft-versus-Host Disease. By combining these findings, we hope to untangle the complexity of acute Graft-versus-Host Disease, ultimately paving the way for the development of novel and more effective treatmen options in patients.

异体造血干细胞移植是现代血液病治疗的基石,但其疗效却因急性移植物抗宿主病(Graft-versus-Host Disease)而大打折扣。在急性移植物抗宿主病中,调理方案引起的上皮损伤导致损伤和病原体相关分子模式的释放,进而引发异体反应性供体T细胞的激活,最终导致健康组织的破坏。主要组织相容性复合体分型和使用组织特异性主要组织相容性复合体缺失的临床前研究的进展,阐明了造血细胞和非造血细胞对急性移植物抗宿主病病理生理学的贡献。与此同时,高通量测序技术使研究人员认识到肠道微生物组和新发现的代谢物对急性移植物抗宿主病病理生理学的重要影响。在这篇综述中,我们将讨论主要组织相容性复合物表达对造血细胞和非造血细胞的影响、对肠道微生物组的影响以及导致急性移植物抗宿主病的代谢改变。我们希望将这些发现结合起来,解开急性移植物抗宿主病的复杂性,最终为开发新的、更有效的患者治疗方案铺平道路。
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引用次数: 0
Allogeneic “Off-the-Shelf” CAR T cells: Challenges and advances 异体 "现成 "CAR T 细胞:挑战与进步
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-07-25 DOI: 10.1016/j.beha.2024.101566

Chimeric antigen receptor (CAR) T cell therapy has shown impressive clinical efficacy in B cell malignancies and multiple myeloma, leading to the approval of six CAR T cell products by the U.S. Food and Drug Administration (FDA) to date. However, broad application of these autologous (patient-derived) CAR T cells is limited by several factors, including high production costs, inconsistent product quality, contamination of the cell product with malignant cells, manufacturing failure especially in heavily pre-treated patients, and lengthy manufacturing times resulting in subsequent treatment delay. A potential solution to these barriers lies in the use of allogeneic “off-the-shelf” CAR T cells produced from healthy donors. Many efforts are underway to make allogeneic CAR T cells a safe and efficacious therapeutic option. In this review, we will discuss the major challenges that have to be addressed to successfully develop allogeneic CAR T cell therapies, specifically graft-versus-host disease (GVHD) and host-mediated immune rejection of the donor cells. Furthermore, we will summarize approaches that have been utilized to overcome these limitations, focusing on the use of gene editing technologies and strategies employing alternative cell populations as the source for allogeneic CAR T cell production.

嵌合抗原受体(CAR)T 细胞疗法在 B 细胞恶性肿瘤和多发性骨髓瘤的临床疗效令人印象深刻,美国食品药品管理局(FDA)迄今已批准了六种 CAR T 细胞产品。然而,这些自体(源自患者)CAR T 细胞的广泛应用受到几个因素的限制,包括生产成本高、产品质量不稳定、细胞产品受到恶性细胞污染、生产失败(尤其是在预处理严重的患者中)以及生产时间过长导致后续治疗延迟。解决这些障碍的潜在办法是使用从健康供体中提取的异体 "现成 "CAR T 细胞。为了使异体 CAR T 细胞成为一种安全有效的治疗选择,我们正在做出许多努力。在这篇综述中,我们将讨论成功开发异体 CAR T 细胞疗法必须应对的主要挑战,特别是移植物抗宿主疾病(GVHD)和宿主介导的供体细胞免疫排斥反应。此外,我们还将总结克服这些局限性的方法,重点是基因编辑技术的使用和采用替代细胞群作为异体 CAR T 细胞生产来源的策略。
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引用次数: 0
HLA typing: A review of methodologies and clinical impact on haematopoietic cell transplantation HLA 分型:造血细胞移植方法和临床影响综述
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-06-01 DOI: 10.1016/j.beha.2024.101562

The importance of the HLA gene system in haematopoietic cell transplant outcomes was established early on and advances in both fields have led to ever increasing success of this clinical therapy. In large part, improvements in the understanding of HLA have been driven by the advancement in typing technologies. Each iteration of typing technology has improved the resolution of HLA typing, and often enabled the identification of polymorphism within the HLA loci. The discovery of the enormous amount of variation in the HLA genes, and the need to be able to characterise this for clinical HLA typing, has often resulted in a move away from one typing method to another more suited to typing of this complexity. Today, the gold standard for HLA typing are methods that can produce definitive HLA typing results.

HLA 基因系统在造血细胞移植结果中的重要性很早就得到了证实,这两个领域的进步使得这种临床疗法的成功率越来越高。在很大程度上,分型技术的进步推动了人们对 HLA 认识的提高。分型技术的每一次更新都提高了 HLA 分型的分辨率,通常还能识别 HLA 位点内的多态性。由于发现了 HLA 基因中的大量变异,而且临床 HLA 分型需要对这些变异进行特征描述,因此通常会从一种分型方法转向另一种更适合这种复杂性分型的方法。如今,HLA 分型的黄金标准是能够产生明确的 HLA 分型结果的方法。
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引用次数: 0
Is HLA-E with its receptors an immune checkpoint or an antigenic determinant in allo-HCT? HLA-E 及其受体是异体肝细胞移植中的免疫检查点还是抗原决定因素?
IF 2.2 4区 医学 Q3 HEMATOLOGY Pub Date : 2024-06-01 DOI: 10.1016/j.beha.2024.101560

Hematopoietic cell transplantation (HCT) represents a potentially curative therapeutic approach for various hematologic and non-hematologic malignancies. Human leukocyte antigen (HLA) matching is still the central selection criterion for HCT donors. Nevertheless, post-transplant complications, in particular graft-versus-host disease (GvHD), relapse of disease and infectious complications, represent a major challenge and contribute significantly to morbidity and mortality. Recently, non-classical HLA class I molecules, especially HLA-E, have gained increasing attention in the context of allogeneic HCT. This review aims to summarize the latest findings on the immunomodulatory role of HLA-E, which serves as a ligand for receptors of the innate and adaptive immune system. In particular, we aim to elucidate how (i) polymorphisms within HLA-E, (ii) the NKG2A/C axis and (iii) the repertoire of peptides presented by HLA-E jointly influence the functionality of immune effector cells. Understanding this intricate network of interactions is crucial as it significantly affects NK and T cell responses and thus clinical outcomes after HCT.

造血细胞移植(HCT)是治疗各种血液学和非血液学恶性肿瘤的潜在疗法。人类白细胞抗原(HLA)配型仍是 HCT 捐赠者的核心选择标准。然而,移植后并发症,尤其是移植物抗宿主病(GvHD)、疾病复发和感染并发症,是一项重大挑战,也是导致发病率和死亡率的重要原因。最近,非经典的 HLA I 类分子,尤其是 HLA-E,在异基因 HCT 中越来越受到关注。本综述旨在总结有关 HLA-E 免疫调节作用的最新发现,HLA-E 是先天性和适应性免疫系统受体的配体。特别是,我们旨在阐明:(i) HLA-E 的多态性;(ii) NKG2A/C 轴;(iii) HLA-E 呈现的肽谱如何共同影响免疫效应细胞的功能。了解这一错综复杂的相互作用网络至关重要,因为它会显著影响 NK 和 T 细胞的反应,从而影响 HCT 后的临床疗效。
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引用次数: 0
期刊
Best Practice & Research Clinical Haematology
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