Abstract
Clinical outcome in antibody-mediated rejection (AMR) shows high inter-individual heterogeneity. Sialylation status of the Fc fragment of IgGs is variable, which could modulate their ability to bind to C1q and/or Fc receptors. In this translational study, we evaluated whether DSA sialylation influence AMR outcomes. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of DSA by Luminex. The sialylation status of total IgG and DSA was quantified using Sambucus nigra agglutinin-based chromatography. All patients had similar levels of sialylation of serum IgGs (~2%). In contrast, the proportion of sialylated DSA were highly variable (median = 9%; range = 0–100%), allowing to distribute the patients in two groups: high DSA sialylation (n = 44; 64%) and low DSA sialylation (n = 25; 36%). The two groups differed neither on the intensity of rejection lesions (C4d, ptc, and g; p > 0.05) nor on graft survival rates (Log rank test, p = 0.99). in vitro models confirmed the lack of impact of Fc sialylation on the ability of a monoclonal antibody to trigger classical complement cascade and activate NK cells. We conclude that DSA sialylation status is highly variable but has not impact on DSA pathogenicity and AMR outcome.
Highlights
Progresses achieved over the last decades in the field of renal transplantation have not significantly improved graft survival [1]
Of the 938 kidney transplant recipients followed in our institutions between September 1st 2004 and September 1st 2012, 69 (7.3%) fulfilled the diagnostic criteria for antibody-mediated rejection (AMR) and were enrolled in the study
Sera banked at the time of the diagnosis of AMR were passed through a G protein column and purified IgG were passed on Sambucus nigra lectin (SNA) column that binds to sialic acid attached to terminal galactose in α-2,6 (Figure 3A)
Summary
Progresses achieved over the last decades in the field of renal transplantation have not significantly improved graft survival [1]. The pathophysiological sequence of AMR starts within recipient’s secondary lymphoid organs [5], in which a T cell-dependent humoral response against mismatched HLA molecules leads to the generation of switched, high affinity, donor-specific antibodies (DSA) [6]. Because of their size, Role of DSA Sialylation Status in AMR. The binding of circulating DSA to directly accessible targets expressed by graft endothelial cells sometimes activate the classical complement pathway [8, 9] but this mechanism is not mandatory for the development of histological lesions [10, 11]. Engagement of the surface Fc receptors of innate immune effectors (including neutrophils, monocytes, and NK cells) by DSA bound to graft microvasculature is sufficient to trigger the release of lytic enzymes, a process named antibody dependent cell cytotoxicity (ADCC) [11, 12]
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