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Donor Specific Antibody Shows Different IgG Subtype in Early versus Late Antibody Mediated Renal Allograft Rejection

Background Early and late antibody mediated rejection (EAMR/LAMR) are immunologically distinct entities and represent major risk factors for allograft survival in renal transplantation. The aim of this study was to describe the nature of donor-specific anti-HLA antibodies (DSA) that mediate EAMR and LAMR, and to correlate these data with DSA mean fluorescence intensity (MFI) response to proteasome-inhibitor (PI) therapy. Methods DSA levels (Day 0 and Day 50 therapy) were determined in 35 (11 EAMR + 24 LAMR) patients who received PI-based AMR therapy (1 or two bortezomib cycles +/- a single rituximab dose (375mg/m2)). All patients had at least 9 months of follow-up after AMR therapy. EAMR was defined as occurring within 6 months after transplantation. All donors and recipients had HLA-A,-B,-C,-DRB1, DRB3/4/5,-DQB1, DQA1 and DPB1 typing by molecular methods, and all cases were transplanted after negative prospective flow T- and B-cell crossmatches. AMR was diagnosed using Antibody Working Group and Banff criteria. Anti-HLA donor-specific antibody were identified by Luminex single-antigen beads (One Lambda) using both the generic IgG and IgG1-4 subtype-specific mAb (PE-conjugated, Southern Biotech). Epitope fingerprints were used to assess the therapeutic response (figures). Results 33 DSA were detected in EAMR (11 class I, 22 class II) and 52 DSA in LAMR (11 class I, 41 class II). DSA Class distribution was 43 anti-HLA class I, 27 anti-HLA DR, 50 anti-HLA DQ and 4 anti-HLA DP. Anti-HLA DQ DSAs were found in 3/11 EAMR vs 18/24 LAMR (p=0.01). IgG1 was detected in all patients, IgG2 was detected in 3/11 EAMR and 5/24 LAMR, IgG3 was present in 15/24 LAMR versus 0/11 EAMR (p=0.007), and IgG4 was detected in 2/11 EAMR vs 6/24 LAMR. There were 4/11 EAMR versus 16/24 LAMR patients with multiple IgG subtypes. The DSA MFI reduction at 50 days after PI therapy was 79±22% in EAMR versus 30±26% in LAMR (p=0.00001).. Summary Late AMR demonstrated: 1) a greater number of de novo DSAs; 2) a greater proportion of anti-HLA class II DSA, especially anti-HLA DQ; 3) a higher proportion of IgG3, the subtype with the highest affinity for complement (C1q) binding; 4) a higher degree of multiple IgG subtypes. 5) lesser response in DSA reduction with PI therapy. Figure. No caption available. Figure. No caption available.