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Clazakizumab treatment effects on peripheral blood and kidney transcriptomes in chronic antibody-mediated rejection

ABSTRACT: There are currently no licenced treatments for antibody-mediated rejection (ABMR), a major cause of late kidney allograft loss. IL-6 is a cytokine that promotes B cell differentiation to plasma cells, T follicular cell (Tfh) polarisation, and monocyte activation, key processes for antibody generation or effector functions. Clazakizumab (CLZ), an IL-6-neutralising antibody, has been used in a phase 2 trial in patients with ABMR, showing potential efficacy in terms of a reduction in donor-specific antibodies and kidney molecular ABMR (MMDx) score. Here we studied the transcriptional changes occurring in paired blood and kidney samples taken following CLZ treatment during this clinical trial. We observed a reduction in ‘FcγR mediated phagocytosis’, ‘complement and coagulation cascades’ and ‘natural killer (NK) cell mediated cytotoxicity’ gene sets in peripheral blood with short-term CLZ treatment, with variable individual responses and some patients showing a rebound in these pathways in longer-term despite ongoing CLZ treatment. We identified a gene module in blood that showed a significant positive correlation with kidney ABMR MMDx score and was down-regulated with CLZ-treatment, potentially identifying a peripheral blood gene set that can be used to non-invasively assess treatment efficacy. In the kidney, CLZ-treatment was associated with a reduction in a “damaged tubule” gene signature and preservation of podocyte signatures, providing further evidence of its therapeutic efficacy in ABMR.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287697 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:The enigmatic natural killer (NK) cells mediate spontaneous cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity via cell surface Fc receptors. The dual functionality of NK cells may enable their participation in chronic active antibody-mediated rejection (CA-ABMR), wherein evidence for complement activation is inconsistent. We RNA sequenced 57 human kidney allograft biopsies to determine whether NK cell cytotoxicity pathway gene set enrichment is an attribute of CA-ABMR. Among the 15,910 intragraft-expressed genes, 60 were uniquely overexpressed in CA-ABMR compared to active antibody-mediated rejection (active-ABMR) or acute T cell-mediated rejection (TCMR), versus no rejection (NR) biopsies. Cell type annotation showed enrichment for T cells and NK cells, and molecular pathways related to T cells and NK cells in CA-ABMR versus active-ABMR biopsies. NK cell cytotoxicity gene set enrichment in CA-ABMR than in ABMR biopsies, but not in TCMR, was confirmed by gene set variation analysis. Cellular deconvolution analysis divulged a higher proportion of NK cells in CA-ABMR compared to active-ABMR, but not in TCMR; immunohistochemistry of 138 consecutive clinically indicated allograft biopsies validated a higher proportion of CD56+ NK cells in CA-ABMR. Principal component analysis of deconvolved immune cell transcriptomes separated CA-ABMR and TCMR from active-ABMR and NR biopsies. NK cell cytotoxicity pathway gene set was found to be enriched in rejection compared to no rejection biopsies in two publicly available kidney allograft microarray datasets. Altogether, CA-ABMR is exemplified by the overexpression of the NK cell pathway, and, surprisingly, compared to active-ABMR, is exemplified by key gene sets that are similar to TCMR.

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The Trifecta study: comparing plasma donor-derived cell-free DNA levels with the molecular phenotype of kidney transplant biopsies

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