PURPOSE: Antibody-mediated rejection (AMR) is caused by antibodies against human leukocyte antigens (HLA) on graft endothelium, and non-HLA antibodies that target endothelial and epithelial proteins. Understanding how kidney tissue protein expression relates to humoral immunity and clinical phenotype would enhance understanding of AMR. The purpose of this study is to integrate protein expression in kidney allograft biopsies with AMR, together with circulating non-HLA and HLA antibodies in biopsy-matched sera and histopathology to better understand the interaction between humoral immunity and kidney proteome.

METHODS: Using protein microarrays, we measured non-HLA antibodies in sera of 14 patients with concurrent AMR and 9 stable controls. Glomeruli and tubules were laser-captured/microdissected from 4 archived biopsies of AMR cases and controls. Proteins were analyzed on Q-Exactive mass spectrometer. Proteins with significantly increased expression in AMR were correlated with non-HLA antibody profiles.

RESULTS: 15 antibodies were significantly increased in AMR sera (q=0.12) compared to controls and few correlated with histopathology (Anti-HLA G, Anti-SRP54, Anti-tropomyosin). 5 of these antibodies were significantly increased (q=0) in sera of an independent cohort of kidney transplant patients with vascular rejection.

We identified 432 glomerular and 680 tubular proteins in biopsy samples. 30 glomerular and 84 tubular proteins were significantly increased in AMR compared to controls (q<0.05). There was preponderance of proteins related to immunity, such as BCAP31, HLA-B, and LCP1. BCAP31 participates in AKT and S6K signaling, implicated in endothelial injury by HLA antibodies. HLA-B44 was detected in AMR case with concomitant circulating HLA-B44 DSA. LCP1 participates in T-cell activation. Non-HLA antibody targets were closely linked to processes occurring in glomerular tissue. Similarly, processes mediated by increased tubular proteins were significantly associated with targets of non-HLA antibodies (p=0.037).

CONCLUSIONS: Our preliminary results identify overexpressed kidney tissue proteins that are putative targets of non-HLA antibodies and are involved in tissue immune response in patients with AMR.

CITATION INFORMATION: Konvalinka A, Chruscinski A, Kim S, Tinckam K, Jurisica I, John R. Interaction Between Kidney Tissue Proteome and Humoral Immunity in Antibody Mediated Rejection. Am J Transplant. 2016;16 (suppl 3).

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