OR50 Complement-binding donor-specific anti-HLA antibodies induce a specific histo-molecular kidney allograft rejection phenotype.

Aim Complement-binding donor-specific anti-HLA antibodies (DSA) have been associated with impaired kidney transplant outcome. We investigated whether they induce a specific kidney allograft rejection phenotype. Methods We prospectively enrolled 931 kidney recipients transplanted between 2011 and 2014, with systematic screening for circulating DSA in the first year post-transplantation. We assessed DSA specificity, mean fluorescence intensity (MFI), C1q-binding capacity and IgG1-4 subclasses using Luminex SAB. All patients underwent allograft biopsy at the time post-transplant DSA detection. The allograft rejection phenotypes were assessed by histopathology, immunochemistry and allograft gene expression (microarray). A model of fully MHC-mismatched male CBA (H-2 k) kidneys transplanted into B6.RAG1−/− (H-2b) immunodeficient mice with adoptive transfer of complement and non-complement-activating DSA was studied. Results We identified 157 (17%) patients with circulating anti-HLA DSA detected in the first year after transplantation, 44 (28%) with complement-binding DSA, and 113 (72%) with non-complement-binding DSA. Patients with complement-binding DSA showed higher MFI levels (9483±747 vs. 2978±278; P < 0.001) and greater prevalence of IgG1 (96% vs. 62%; P < 0.001) and IgG3 (57% vs. 17%; P < 0.001) subclasses than patients with non-complement-binding DSA. The histo-molecular phenotype of complement-binding DSA allograft rejection was characterized by increased microvascular infiltration by NK cells ( P < 0.001), monocyte/macrophages ( P < 0.001), greater complement deposition ( P < 0.001), and selective changes in gene expression including monocyte/macrophage, interferon-gamma and endothelial activation (CXCL11, CCL4, MS4A6A, MS4A7, GBP1; P < 0.01), as compared with patients with non-complement-binding DSA. This rejection phenotype was distinct from that of patients with non-complement-binding DSA and without DSA in unsupervised principal component analysis. Mice receiving complement-activating DSA reproduced the human complement-binding antibody-mediated histo-molecular rejection phenotype. Conclusions Circulating complement-binding anti-HLA DSA induce a specific histo-molecular phenotype of kidney allograft rejection. [ABSTRACT FROM AUTHOR]