Background: Antibody-mediated rejection (ABMR) is a major pathway associated with late graft loss. Although serum de novo donor-specific HLA antibodies are frequently observed in ABMR, their presence does not predict if microvascular inflammation (MI) will also be present in the graft. The aim of this study is to test the hypothesis that serum proteins can detect the presence of MI associated with clinical ABMR using a novel aptamer technology.

Methods: Aptamers are short nucleic acid molecules designed to bind to specific target proteins, similar to a monoclonal antibody. SOMAmersTM (SOMAlogicTM, Boulder, CO) are a specific type of modified aptamer that bind to their target protein with extremely high affinity. Utilizing this aptamer array platform we simultaneously assessed 1,129 serum protein in 50ul of sera. This method has a median limit-of-detection of 1.6 pg/mL and a median dynamic range of 4 logs.

Serum proteins in patients with biopsy-proven normal histology at 2 years post-transplant and maintaining normal graft function for the next 10 years (n=20) were compared to those with de novo donor-specific antibody (dnDSA)-related clinical AMR (n=10).

Results: 45 proteins were identified with differential expression between the two patient groups (p<0.01); with an overall increase in proteins related to inflammation and endothelial activation in patients with clinical AMR. Upregulated inflammatory-associated proteins included IL-6 soluble receptor α (p<0.002) and CXCL16 (p<0.01). Of particular interest was an increase in delta-like protein 1 [Dll-1 (p<0.002)], a Notch-1 ligand promoting the differentiation of B cells into antibody-secreting cells, and galectin-3 (p<0.01), a lectin expressed by activated T and B cells that facilitates chemotaxis and is a fibroblast mitogen. An increase in ephrin A4 (p<0.0003), linked to mediating adhesion between platelets, monocytes, and endothelial cells, and IL-1 receptor like 1 (p<0.002), the IL-33 receptor that drives endothelial activation was also detected.

Conclusion: Serum proteins can reflect MI in patients with clinical ABMR and be quantitatively assessed using aptamer technology. Ongoing studies will determine whether these proteins are also present in patients with subclinical ABMR and assess their specificity. Once validated, they may prove useful for detecting ABMR and monitoring the response to therapy.

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