Background: Viral infections represent significant morbidity factors for KTx Pts. Ab-dependent cell-mediated cytotoxicity (ADCC) is a major pathway to eliminate virally infected cells and is mediated primarily by NK cells. IdeS cleaves all 4 human IgG subclasses at the hinge region of IgG heavy chains, critical for ADCC. A clinical trial to remove anti-HLA Ab by IdeS in HS KTx Pts is now underway. Here, we investigate the impact of IdeS on anti-CMV immunity in vitro and in IdeS-treated Pts. Methods: Whole blood from 5 CMV sero(+) normal individuals was submitted for the CMV-specific T & NK cell-cytokine flow cytometry (CMV-T/NK-CFC) where blood was incubated with CMV lysate w/ Brefeldin A w/ or w/o IdeS (0.1-10mg/ml) followed by staining intracellular IFNg. Results were expressed as IFNg+ cell% in CD4+ T & CD56+ NK cells. Pre- & post-IdeS sera from 13 and blood from 2 sero(+) Pts were submitted for anti-CMV IgG-ELISA & the CMV-T/NK-CFC, respectively. Results: IFNg+ NK (31±10% vs. 4±2%, p=0.02) and T (3.2±2.2% vs. 0.7±0.1%, p=0.02) cell% significantly increased when blood was incubated with CMV lysate. The elevated CMV-NK was significantly reduced by IdeS in a dose dependent manner with complete inhibition seen at 1mg/ml (therapeutic level) (24±17%, p=0.04 at 0.1mg/ml; 2.0±0.6%, NS at 1mg/ml; 1.8±0.6%, NS at 10mg/ml), while minimal reduction was seen in T cells (2.3±0.5%, p=0.02; 1.9±0.8%, p=0.04; 1.9±0.8%, p=0.04, respectively). All 13 Pts were (+) for anti-CMV IgG pre-IdeS (29±35 IU/ml), but became (-) at D1 (0.2±0.2 IU/ml), and then were again (+) at D28 (21±16 IU/ml) after IVIG infusion. CMV-NK were positive (>0.5%) in 2 pre-IdeS Pts (1.3%, 14.9%) but were (-) at D1 (0.1%, 0.1%), and then began to return to baseline by D28 (1.1%, 0.6%). In contrast, CMV-T remained positive (>0.2%) at all these time points; 0.6, 1.4 & 0.4% in Pt1; 1.9, 2.4 & 1.2% in Pt2, respectively. Conclusions: IdeS effectively cleaves anti-CMV antibody in IdeS-treated Pts, suggesting inhibition of ADCC-mediated anti-CMV immunity, that is restored by 1M post-IdeS after IVIg infusion. Importantly, IdeS does not inhibit CMV-T cell activity as this is not Ab-dependent.

CITATION INFORMATION: Shin B.-H, Ge S, Chu M, Choi J, Winstedt L, Kjellman C, Louie S, Vo A, Peng A, Jordan S, Toyoda M. IdeS, an IgG Endopeptidase, Effectively Cleaves Anti-CMV IgG, Resulting in Inhibition of Antibody (Ab)-Mediated NK Cell Activation in Kidney Transplant Patients (KTX Pts). Am J Transplant. 2017;17 (suppl 3).

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