Association of HLA Mismatches and Histology Suggestive of Antibody-Mediated Injury in the Absence of Donor-Specific Anti-HLA Antibodies

Abstract

Background: The histology of antibody-mediated rejection after kidney transplantation is observed frequently in absence of detectable donor-specific anti-HLA antibodies. While 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. Methods: To study this, HLAMatchmaker, EMS-3D, HLA-EMMA and PIRCHE-II tools were used 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 donorspecific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy Results: 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 absence of donor-specific anti-HLA antibodies. This association was neither dependent 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. Conclusions: 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.

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II

“…However, the most detrimental effects on allografts were observed in the presence of both HLA and non-HLA antibodies ( 35 ). The association of HLA mismatches and histology suggestive of ABMR in absence of DSA has been studied in 121 renal transplant recipients using multiple tools such as HLAMatchmaker, PIRCHE-II and HLA- EMMA ( 29 ). The study indicated that the lesions associated with histology of ABMR are not specific to antibody involvement and can be caused by immune activation through donor-recipient HLA mismatch ( 29 ).…”

Novel insights in the clinical management of hyperimmune patients before and after transplantation

“…Recent evidence indicates the involvement of direct natural killer (NK) cell activation in the occurrence of microvascular inflammation in the absence of DSAs ( Callemeyn et al, 2022 ). Moreover, it has been shown that donor-recipient HLA mismatch is at least partially involved in developing the histological presentation of AMR and its defining lesions in an HLA antibody–independent process, regardless of the way of calculating the donor-recipient HLA disparity ( Senev et al, 2019 , Senev et al, 2022 ; Palmieri et al, 2021 ). Thus, the lesions suggestive of antibody activity are not specific for antibody involvement but probably due to primary T cell activation as an initiating process ( Senev et al, 2019 ).…”

Histologic and molecular features of antibody-mediated rejection

“…Senev et al [16] studied the importance of other underlying pathophysiologic processes in AMR, including HLA/non-HLA antibodies, missing self, and HLA mismatches in the dichotomy of AMR and TCMR, given that the authors have found that HLA mismatches are independently associated with AMR histology even in the absence of circulating HLA antibodies. Also, supported by findings that a substantial portion of these cases also had TCMR, the authors suggest a possible involvement of T-cell activation in AMR that occurs in the absence of antibody or complement.…”