Transcriptomic Immune Signatures in Chronic Active Antibody-Mediated Rejection: NK Cells and More

View Full Size

• Download Figure
• Download figure as PowerPoint slide

As the primary cause of long-term allograft loss, chronic active antibody-mediated rejection (CA-ABMR) is a critical focal point of kidney transplant research. Recent studies have increasingly focused on molecular mechanisms and cell types that may distinguish CA-ABMR from other forms of rejection as a means of identifying potential therapeutic targets or predictive biomarkers; however, the factors underlying the development of CA-ABMR remain up for debate.

In their recent article, Transcriptomic Signatures of Chronic Active Antibody-Mediated Rejection Deciphered by RNA Sequencing of Human Kidney Allografts, Shah and colleagues performed bulk RNA sequencing of kidney allograft biopsies to provide a comprehensive look at transcriptomic differences among CA-ABMR, active ABMR, and T cell-mediated rejection (TCMR) compared with stable allografts (1). They identified a cytolytic gene signature that is increased in CA-ABMR compared with both no rejection and active ABMR but shared with TCMR, and the authors mapped this signature to natural killer (NK) cells using a gene set enrichment analysis and deconvolution analysis. As confirmation of this NK cell signature, they were able to find the same enhanced gene expression in several publicly available datasets and identified increased proportions of NK cells in biopsies from CA-ABMR and TCMR kidney allograft recipients, compared with active ABMR, through direct immunohistochemistry.

While this study effectively pairs high throughput analysis with external validation to address an important aspect of kidney transplant rejection, it has several notable limitations. The focus on NK cells at the expense of other immune populations represents a missed opportunity given the breadth of the dataset. Indeed, the authors identify significant shifts in a variety of immune cell subsets between both active ABMR/CA-ABMR and TCMR/CA-ABMR. Given that the authors were able to image NK cells directly in allograft biopsies, along with some discrepancy between the immune cell proportions determined through deconvolution versus by immunohistochemistry, there is also a question of whether this type of high throughput analysis is required or suitable for cell identification. Similarly, it is curious that the authors did not address the possibility of CD8⁺ T cells as the source of the increased cytolytic signature in CA-ABMR, particularly given the extensive evidence showing that these cells are significantly increased in CA-ABMR and are linked to the likelihood of allograft failure (2–4).

From a methodologic standpoint, the significantly longer time between transplant and indication biopsy for CA-ABMR cases versus comparator groups represents an important confounder that could limit the generalizability of the results, particularly given the cross-sectional nature of the study. Additionally, the decision to define donor-specific antibodies’ positivity on the basis of mean fluorescent intensity, as well as incomplete donor human leukocyte antigen allele genotyping, leaves room for possible cases of mixed rejection within the TCMR group, which could explain some of the observed similarity between CA-ABMR and TCMR in this study.

Despite these considerations, the NK cell signature identified in CA-ABMR is robust and adds another layer to the existing literature in support of NK cell importance in ABMR at the transcriptional level. Overall, this research represents an important contribution to the timely question of what distinguishes CA-ABMR from its other manifestations and provides a transcriptomic dataset that could be mined in future studies.

View Full Size

• Download Figure
• Download figure as PowerPoint slide