Addressing the heterogeneity of antibody-mediated allograft rejection by identifying phenotypes based on pathophysiology is critical for improving outcomes in transplantation. We investigated whether complement-binding anti-HLA DSA induce specific rejection phenotype and influence response to complement targeting therapy.

We prospectively enrolled 931 kidney recipients transplanted between 2011 and 2014 in 2 Paris centers, with systematic screening for anti-HLA DSA in the first year post-transplantation. All patients underwent allograft biopsy at the time of detection of DSA to assess rejection phenotypes by histopathology, immunochemistry and allograft gene expression analysis using microarray. A model of fully MHC-mismatched male CBA (H-2k) kidneys transplanted into B6.RAG1-/- (H-2b) immunodeficient mice with adoptive transfer of complement and non-complement-binding DSA was studied. The effect of complement inhibition therapy (Eculizumab) on allograft injury phenotype was assessed in 2 prospective studies (N=70).

The histo-molecular phenotype of allograft rejection in patients with C1q-binding DSA (N=44/157; 28%) was characterized by increased microvascular infiltration by NK cells (3.9±1.5 vs. 0.4±0.2 NK cells per 10 high-power fields; P<0.001), monocyte/macrophages (5.8±2.7 vs. 2.4±1.9 per peritubular capillary and 2.2±1.5 vs. 0.9±0.7 per glomeruli; P<0.001), greater prevalence of complement deposition (63% vs. 19%; P<0.001) and selective changes in allograft gene expression including interferon-gamma and endothelial activation (CXCL11, CCL4, MS4A6A, MS4A7, GBP1; P<0.01), as compared with patients with non-C1q-binding DSA (N=113/157; 72%). This phenotype was distinct from that of patients with non-C1q-binding DSA and without DSA in unsupervised clustering and PCA. Mice receiving complement-binding DSA reproduced the human complement activating antibody-mediated histo-molecular allograft rejection phenotype. Eculizumab abrogated the histo-molecular phenotype induced by C1q-binding DSA and showed no effect on allograft injury in patients with non-C1q-binding DSA.

Circulating complement-binding anti-HLA DSA induce a distinct histo-molecular phenotype of kidney allograft rejection that can be specifically reversed by complement inhibition therapy.

CITATION INFORMATION: Lefaucheur C, Sis B, Viglietti D, Hidalgo L, Aubert O, Glotz D, Legendre C, Zeevi A, Halloran P, Loupy A. Complement Activating Anti-HLA Antibodies: Identification of Specific Histo-Mmolecular Phenotype of Rejection for Complement-Targeting Therapy. Am J Transplant. 2017;17 (suppl 3).

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