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Single-Cell RNA Sequencing to Assess the Effect of IL-6 Receptor Blockade in Kidney Transplantation

A. Zarinsefat, P. Rashmi, A. Da Silva, T. Sigdel, S. Chandran, Q. Tang, J. Ye, F. Vincenti, M. Sarwal

University of California San Francisco, San Francisco, CA

Meeting: 2020 American Transplant Congress

Abstract number: 208

Keywords: Genomics, Immunosuppression, Inflammation, Rejection

Session Information

Date: Saturday, May 30, 2020

Session Name: Basic: Acute Rejection

Session Time: 3:15pm-4:45pm

 Presentation Time: 3:39pm-3:51pm

Location: Virtual

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*Purpose: Prospective randomized study of IL-6R blockade with Tocilizumab for treatment of subclinical inflammation (SCI) in renal transplantation, reveals unique profiles of resting and stimulated PBMCs by multiplex single-cell RNASeq (scRNA-seq).

*Methods: Fifteen patients were sequentially enrolled in a prospective randomized clinical trial of Tocilizumab vs. standard of care (SOC; observation only) for SCI at the time of stable kidney allograft function, as assessed by the 6 month protocol biopsy. Serial PBMC samples at enrollment, and at sequential time points until 1 year later, were profiled by multiplexed droplet scRNA-seq (Mux-Seq) on the 10X Genomics platform, either as resting cells or stimulated with CD3/CD28 antibodies. Cell genotyping was simultaneously performed using SNP arrays and Demuxlet was used for identifying individual cell identities. Seurat/SingleR packages and UMAP were used for Mux-Seq analysis. Patients had a follow-up biopsy 1 month and 12 months later, which was scored by Banff, and Tregs were measured in the circulation over time.

*Results: Following cell clustering using UMAP, multiple distinct PBMC cell subsets inclusive of different T, B, NK, Treg, and monocytes were noted (Fig. 1). IL-6 gene expression of stimulated cells from patients receiving Tocilizumab resulted in loss of IL-6 expression (Fig. 2), when compared to SOC patients. Other inflammatory genes also show marked loss of expression in Tocilizumab-treated stimulated cells, including interferon-gamma (IFNG) (Figure 2). Tregs expanded over time, and biopsy histology showed mild reduction in SCI in a few patients on Tocilizumab.

*Conclusions: Tocilizumab treatment for SCI results in mild reduction of graft inflammation by histology, expansion of peripheral Tregs, changes in different PBMC subsets over time, and marked reduction of IL-6, IL-6R, and pro-inflammatory gene expression in stimulated rather than resting PBMCs. Mux-Seq reduces batch variation, sequencing costs, and sample input. These results support unique cell-subset compositions with IL-6R blockade and possibly greater value in priming the allograft with Tocilizumab, prior to the development of allograft injury.

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To cite this abstract in AMA style:

Zarinsefat A, Rashmi P, Silva ADa, Sigdel T, Chandran S, Tang Q, Ye J, Vincenti F, Sarwal M. Single-Cell RNA Sequencing to Assess the Effect of IL-6 Receptor Blockade in Kidney Transplantation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/single-cell-rna-sequencing-to-assess-the-effect-of-il-6-receptor-blockade-in-kidney-transplantation/. Accessed March 7, 2021.

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