Background: Ab-mediated rejection (ABMR) is a major obstacle in HS KTx Pts. ADCC is a mechanism responsible for ABMR. IdeS cleaves all 4 human IgG subclasses at the hinge region of heavy chains, critical for ADCC. A clinical trial to remove anti-HLA Ab using IdeS in HS KTx Pts is now underway. We previously showed complete inhibition of Ab-mediated NK cell activation and cytotoxicity by IdeS in vitro using normal blood. Here, we investigated the effects of Ides on these Ab-mediated NK cell activities in IdeS-treated Pts. Methods: Pre- & post-IdeS anti-HLA Ab levels in 5 pts were measured by luminex. The levels (total class I & II) were expressed as score; Score 10, 5, 2 & 0 for SFI>200K, 100K-200K, <100K & 0, respectively, are given to each detected Ab, and the sum of these are the final score for serum w/ multiple Abs. Allo-CFC to assess Ab-mediated NK activation was performed by incubating normal blood w/ irradiated allo-peripheral blood mononuclear cells (PBMCs) pre-treated w/ pre- & 1D, 1M, 3M post-IdeS Pt sera followed by intracellular IFNγ detection by flow cytometry (CFC) & IFNγ+ NK cells% enumeration. ADCC where normal PBMCs (effector) were incubated w/ pre-labeled CD19+ Farage B cells (FB, target) followed by 7-AAD staining was performed w/ pre- & post-IdeS Pt sera, and 7-AAD+FB cell% were enumerated. Results: Pre-IdeS anti-HLA Ab scores significantly decreased at D1 post-IdeS (287±125 vs. 36±51, p<0.01), and then returned to base line by M1 (288±180). IFNγ+ NK cell% in the CFC w/ pre-IdeS serum significantly decreased compared to D1 post-IdeS serum (7.8±4.8% vs. 2.2±1.7%, p=0.03), but became similar to the base line w/ 1M (7.5±5.1%), 3M (6.7±4.5%) & 6M (8.9±3.1%) post-IdeS serum. Pre- & post-IdeS sera from 2 Pts were tested for ADCC. 7-AAD+ FB cells% decreased in the ADCC w/ 1D post-IdeS compared to pre-IdeS sera, and then returned to the base line w/ 1M post-IdeS serum (3.0% to 1.9% to 3.8% in Pt1, 5.0% to 3.4% to 10.9% in Pt2). Conclusions: IdeS effectively cleaves anti-HLA Ab in IdeS-treated Pts, resulting in inhibition of Ab-mediated NK cell activation and ADCC in vitro. These suggest that IdeS could contribute to the reduction of ADCC-mediated ABMR in HS KTx Pts.

CITATION INFORMATION: Ge S, Chu M, Choi J, Louie S, Kang A, Vo A, Peng A, Jordan S, Toyoda M. IdeS, an IgG Endopeptidase, Effectively Cleaves Anti-HLA Antibody (Ab), Resulting in Inhibition of Anti-HLA Ab-Mediated NK Cell Activation and Ab-Dependent Cell-Mediated Cytotoxicity (ADCC) in HLA-Sensitized Kidney Transplant Patients (HS KTx Pts). Am J Transplant. 2017;17 (suppl 3).

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