Mella Alberto, Lavacca Antonio, Dodoi Diana Teodora, Presta Roberto, Fop Fabrizio, Campagna Marco, Manzione Ana Maria, Dolla Caterina, Gallo Ester, Abbasciano Isabella, Gai Chiara, Camussi Giovanni, Barreca Antonella, Caorsi Cristiana, Giovinazzo Gloria, Biancone Luigi
Renal Transplantation Center, "A. Vercellone," Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy.
Department of Medical Sciences, University of Turin, Turin, Italy.
Transplant Direct. 2024 May 16;10(6):e1638. doi: 10.1097/TXD.0000000000001638. eCollection 2024 Jun.
Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs.
Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included.
Differently from TG/DSA, TG/DSA showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA, whereas TG/DSA tends to maintain or increase periglomerular/interstitial infiltration.
In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.
移植肾小球病（TG）是慢性抗体介导性排斥反应的标志，但通常在没有抗人白细胞抗原（HLA）供者特异性抗体（DSA）的情况下发生，推测其他DSA可能是组织损伤的效应因子。最近，我们报道了白细胞介素-6（IL-6）受体阻滞剂托珠单抗（TCZ）对TG/DSA有积极作用。在本研究中，我们调查了TCZ对一组未检测到抗HLA DSA的TG病例的影响。
纳入对因慢性抗体介导性排斥反应接受TCZ作为一线治疗的无抗HLA DSA的TG病例（TG/DSA）进行单中心回顾性分析，通过临床、方案活检和基因表达分析进行评估。
与TG/DSA不同，TG/DSA在12个月时估计肾小球滤过率逐渐降低，之后微血管炎症或C4d无明显改变。在TCZ治疗后的活检中未发现TG/DSA中记录的紧密连接蛋白-1、醛糖还原酶家族1成员C3和钙/钙调蛋白依赖性丝氨酸蛋白激酶上调。微血管炎症的减轻与TG/DSA中自然杀伤细胞减少有关，而TG/DSA倾向于维持或增加肾小球周围/间质浸润。
在没有抗HLA DSA的情况下，IL-6受体阻断似乎不会改变TG的行为。这些结果与观察性研究以及之前在与抗HLA DSA相关的TG中使用IL-6抑制剂的试验结果不一致。这些数据可能支持TG存在不同机制的假说（包括自然杀伤细胞可能不同的作用），并建议根据患者的抗供者血清学状态仔细选择TG患者进行临床试验或非标签治疗。
