Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Mueller, Franco B.; Yang, Hua; Lubetzky, Michelle; Verma, Akanksha; Lee, John R; Dadhania, Darshana; Xiang, Jenny; Salvatore, Steven; Seshan, Surya V.; Sharma, Vijay Kumar; Elemento, Olivier; Suthanthiran, Manikkam; Muthukumar, Thangamani

doi:10.1172/jci.insight.128014

Cited by 36 publications

(44 citation statements)

References 86 publications

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“…Specifically, kidney macrophages have been characterized both transcriptionally ( 9 ) and functionally ( 10 , 11 ), and they are implicated in numerous kidney disease processes, including nephritis ( 12 ), acute kidney injury ( 13 ), and kidney fibrosis ( 14 ). It has also been shown that, during an episode of acute cell–mediated rejection, kidney allografts are typically heavily infiltrated with macrophages in addition to T lymphocytes ( 15 , 16 ) — a finding corroborated by the association of macrophage and dendritic cell–specific transcriptomes with T cell–mediated rejection ( 17 ). These data, thus, suggest a potential role of intragraft macrophages in shaping the host immune response to the transplanted kidneys ( 18 ).…”

Section: Introductionmentioning

confidence: 87%

Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection

Dangi¹,

Natesh²,

Husain³

et al. 2020

JCI Insight

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Myeloid cells are increasingly recognized as major players in transplant rejection. Here, we used a murine kidney transplantation model and single cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques, including machine learning, we demonstrate that kidney allograft–infiltrating myeloid cells followed a trajectory of differentiation from monocytes to proinflammatory macrophages, and they exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl , a member of the receptor tyrosine kinase family Tyro3/Axl/Mertk (TAM). Using kidney transplant recipients with Axl gene deficiency, we further demonstrate that Axl augmented intragraft differentiation of proinflammatory macrophages, likely via its effect on the transcription factor Cebpb. This, in turn, promoted intragraft recruitment, differentiation, and proliferation of donor-specific T cells, and it enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell Axl expression identified by single cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and it presents a potentially novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.

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Section: Introductionmentioning

confidence: 87%

Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection

Dangi¹,

Natesh²,

Husain³

et al. 2020

JCI Insight

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“…Upregulation of NCF2 in renal biopsies indicates that enhanced oxidative stress is an essential mechanism. Through cleavage by Casp1, interleukin-1 and -18 are secreted from the cell to induce the inflammatory response in neighbouring cells, [49] resulting in intense inflammatory, immune responses and acute rejection [3]. Increased expression of GBP1 is also reported in chronic rejection patients when compared with recipients with stable renal function [15]; however, the involvement of GBP1 in immune responses has not been studied.…”

Section: Discussionmentioning

confidence: 99%

“…Pathological diagnosis is the best approach to assess disease classification and differentiate complications. However, many cases are diagnostically difficult since disease processes share nonspecific mechanisms, including innate immunity [3,4], inflammation [5][6][7], and microcirculation remodelling [8].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics analyses on the immune status of renal transplant patients, a systemic research of renal transplantation

et al. 2020

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Background: Kidney transplantation is the most effective treatment for end-stage renal disease. Allograft rejections severely affect survivals of allograft kidneys and recipients. Methods: Using bioinformatics approaches, the present study was designed to investigate immune status in renal transplant recipients. Fifteen datasets from Gene Expression Omnibus (GEO) were collected and analysed. Analysis of gene enrichment and protein-protein interactions were also used. Results: There were 40 differentially expressed genes (DEGs) identified in chronic rejection group when compared with stable recipients, which were enriched in allograft rejection module. There were 135 DEGs identified in acute rejection patients, compared with stable recipients, in which most genes were enriched in allograft rejection and immune deficiency. There were 288 DEGs identified in stable recipients when compared to healthy subjects. Most genes were related to chemokine signalling pathway. In integrated comparisons, expressions of MHC molecules and immunoglobulins were increased in both acute and chronic rejection; expressions of LILRB and MAP 4 K1 were increased in acute rejection patients, but not in stable recipients. There were no overlapping DEGs in blood samples of transplant recipients.Conclusion: By performing bioinformatics analysis on the immune status of kidney transplant patients, the present study reports several DEGs in the renal biopsy of transplant recipients, which are requested to be validated in clinical practice.

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“…Gene expression signatures of rejection were first discovered using microarray analysis 2 . However a number of research groups have now assessed gene expression signatures in transplant biopsies placed in an RNA preservative, using a variety of methods, not only microarray analysis [3][4][5][6][7][8][9][10] , but also quantitative real-time polymerase chain reaction (qRT-PCR) [11][12][13] and RNA sequencing 9,14,15 . Further validation of gene signatures for diagnostic use has not proceeded however, partly because a renal transplant biopsy is an invasive procedure that yields a limited amount of tissue.…”

Section: Amrmentioning

confidence: 99%

Technical considerations when designing a gene expression panel for renal transplant diagnosis

Toulza

Dominy

Cook

et al. 2020

Sci Rep

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Gene expression analysis is emerging as a new diagnostic tool in transplant pathology, in particular for the diagnosis of antibody-mediated rejection. Diagnostic gene expression panels are defined on the basis of their pathophysiological relevance, but also need to be tested for their robustness across different preservatives and analysis platforms. The aim of this study is the investigate the effect of tissue sampling and preservation on candidate genes included in a renal transplant diagnostic panel. Using the NanoString platform, we compared the expression of 219 genes in 51 samples, split for formalin-fixation and paraffin-embedding (FFPE) and RNAlater preservation (RNAlater). We found that overall, gene expression significantly correlated between FFPE and RNAlater samples. However, at the individual gene level, 46 of the 219 genes did not correlate across the 51 matched FFPE and RNAlater samples. Comparing gene expression results using NanoString and qRT-PCR for 18 genes in the same pool of RNA (RNAlater), we found a significant correlation in 17/18 genes. Our study indicates that, in samples from the same routine diagnostic renal transplant biopsy procedure split for FFPE and RNAlater, 21% of 219 genes of potential biological significance do not correlate in expression. Whether this is due to fixatives or tissue sampling, selection of gene panels for routine diagnosis should take this information into consideration.

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Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Cited by 36 publications

References 86 publications

Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection

Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection

Bioinformatics analyses on the immune status of renal transplant patients, a systemic research of renal transplantation

Technical considerations when designing a gene expression panel for renal transplant diagnosis

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