Diebold Matthias, Mayer Katharina A, Hidalgo Luis, Kozakowski Nicolas, Budde Klemens, Böhmig Georg A
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland.
Transplantation. 2025 Apr 1;109(4):610-621. doi: 10.1097/TP.0000000000005187. Epub 2024 Aug 28.
In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.
在肾移植中，持续的同种免疫过程（通常由HLA不相容性引发）可触发慢性移植排斥反应，影响微循环和肾小管间质。持续的炎症可能导致进行性、不可逆的移植物损伤，最终导致移植物功能障碍和移植失败加速。大量的实验和转化研究已经阐明了驱动排斥反应的不同免疫机制之间的复杂相互作用，其中抗体介导的排斥反应（AMR）是一种被广泛研究的排斥反应变体。在微血管炎症（AMR的一个标志性病变）中，自然杀伤（NK）细胞已成为关键的效应细胞。免疫组织学证据、大量和空间转录组学以及功能遗传学均支持它们的重要作用。尽管进行了大量研究，但对于获批的排斥反应治疗仍存在大量未满足的需求，许多试验都产生了阴性结果。然而，目前有几种有前景的疗法正在研究中，包括felzartamab，一种靶向表面分子CD38的单克隆抗体，该分子在NK细胞和产生抗体的浆细胞中高度表达。在一项针对晚期AMR的探索性2期试验中，这种化合物已显示出在解决分子和形态学排斥活性及损伤方面的潜力，主要是通过靶向NK细胞效应功能。这些发现为有效治疗带来了希望，并强调了进一步开展针对慢性移植排斥反应的关键试验的必要性。
