The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation.

To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA–derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy.

In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell–mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies.

The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch.

肾移植后抗体介导的排斥反应的组织学经常在缺乏可检测的供体特异性抗 HLA 抗体的情况下观察到。尽管人们对非 HLA 抗体在这种表型中的作用非常感兴趣，但 HLA 错配是否在这种微循环炎症表型中发挥独立于抗体的作用仍不清楚。

为了研究这一点，我们使用 HLAMatchmaker、三维静电错配评分、HLA 溶剂可及氨基酸错配和错配供体 HLA 衍生 T 细胞表位靶标等工具，通过可用的活检确定 893 名肾移植受者的 HLA 分子错配程度跟进。应用多变量 Cox 比例风险模型来量化不同类型 HLA 错配评分的特定原因风险比，以在缺乏供体特异性抗 HLA 抗体的情况下开发抗体介导的排斥反应或抗体介导的排斥反应的组织学。在所有生存分析中，患者在最后一次活检时进行了审查。

总共有 121 名 (14%) 患者在缺乏供者特异性抗 HLA 抗体的情况下出现了抗体介导的排斥反应，其中 44 名 (36%) 患者伴有 T 细胞介导的排斥反应。在多变量 Cox 分析中，HLA 错配程度的所有不同计算都与在缺乏供体特异性抗 HLA 抗体的情况下抗体介导的排斥反应的发展组织学相关。这种关联既不依赖于缺失自身的存在（可能与自然杀伤细胞激活有关），也不依赖于从头HLA 抗体的形成。此外，在没有抗 HLA 抗体的情况下，肾小球炎和补体 C4d 在管周毛细血管中的沉积与 HLA 不匹配的程度相关。

在没有循环抗 HLA 抗体的患者中也观察到抗体介导的排斥反应的组织学及其定义的病变，并且与 HLA 不匹配的程度相关。