Department of Nephrology, Hospital del Mar, Barcelona, Spain.
Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
Front Immunol. 2021 Jul 6;12:703457. doi: 10.3389/fimmu.2021.703457. eCollection 2021.
Correlation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved.
We retrospectively assessed patients with transplant biopsies scored following Banff'15 classification. Pre- and post-transplant serum samples were checked for HLA and non-HLA antibodies [MICA-Ab, angiotensin-II type-1-receptor (ATR)-Ab, endothelin-1 type-A-receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)]. We also analyzed HLA epitope mismatches (HLA-EM) between donors and recipients to explore their role in ABMR histology (ABMR) with and without HLA-DSA.
One-hundred eighteen patients with normal histology (n = 19), ABMR (n = 52) or IFTA (n = 47) were studied. ABMR patients were HLA-DSA (n = 38, 73%) or HLA-DSA (n = 14, 27%). Pre-transplant HLA-DSA and ATR-Ab were more frequent in ABMR compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMRDSA cases showed non-HLA antibodies. ABMRDSA and ABMRDSA cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMRDSA but not with ABMRDSA. Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31-10.37], p = 0.013) and ATR-Ab (OR: 5.47 [1.78-16.76], p = 0.003) were independent predictors of ABMRDSA.
In conclusion, pre-transplant ATR-Ab is frequently found in ABMRDSA patients. However, ATR-Ab, MICA-Ab, ETAR-Ab or EC-XM are rarely found among ABMRDSA patients. Pre-transplant ATR-Ab may act synergistically with preformed or HLA-DSA to produce ABMRDSA but not ABMRDSA. HLA epitope mismatch associates with ABMRDSA compared with ABMRDSA, suggesting factors other than HLA are responsible for the damage.
抗体介导的排斥反应（ABMR）与循环 HLA 供体特异性抗体（HLA-DSA）之间存在很强的相关性，但在肾移植（KT）受者中并不完美，这使得 HLA-DSA 或非 HLA 抗体可能导致 ABMR 未被检测到。详细评估 HLA 配型程度以及在 KT 中识别非 HLA 抗体有助于解析相关抗体。
我们回顾性评估了根据 Banff'15 分类进行移植活检评分的患者。检测了移植前和移植后的血清样本中的 HLA 和非 HLA 抗体[MICA-Ab、血管紧张素 II 型 1 受体（ATR）-Ab、内皮素 1 型 A 受体（ETAR）-Ab 和与原代主动脉内皮细胞（EC-XM）的交叉匹配]。我们还分析了供体和受体之间的 HLA 表位错配（HLA-EM），以探讨其在有和无 HLA-DSA 的 ABMR 组织学中的作用。
研究了 118 名组织学正常（n = 19）、ABMR（n = 52）或 IFTA（n = 47）的患者。ABMR 患者中 HLA-DSA（n = 38，73%）或 HLA-DSA（n = 14，27%）。与 IFTA 和组织学正常病例相比，ABMR 患者的移植前 HLA-DSA 和 ATR-Ab 更为常见（p = 0.006 和 0.003），其他非 HLA 抗体则无差异。只有 3 例 ABMRDSA 病例显示存在非 HLA 抗体。ABMRDSA 和 ABMRDSA 病例的活检变化和移植物存活率相似。HLA-EM 总 II 类和 DRB1 均与 ABMRDSA 相关，但与 ABMRDSA 无关。多变量分析显示，移植前 HLA-DSA（OR：3.69 [1.31-10.37]，p = 0.013）和 ATR-Ab（OR：5.47 [1.78-16.76]，p = 0.003）是 ABMRDSA 的独立预测因子。
总之，移植前 ATR-Ab 在 ABMRDSA 患者中经常发现。然而，ABMRDSA 患者中很少发现 ATR-Ab、MICA-Ab、ETAR-Ab 或 EC-XM。移植前 ATR-Ab 可能与预先形成的或 HLA-DSA 协同作用，产生 ABMRDSA，但不会产生 ABMRDSA。与 ABMRDSA 相比，HLA 表位错配与 ABMRDSA 相关，提示 HLA 以外的其他因素可能导致损伤。
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