Genomics of BK Viremia in Kidney Transplant Recipients

Lubetzky, Michelle; Bao, Yi; Broin, Pilib Ó; Marfo, Kwaku; Ajaimy, Maria; Aljanabi, Aws; Boccardo, Graciela de; Golden, Aaron; Akalin, Enver

doi:10.1097/01.tp.0000437432.35227.3e

Cited by 20 publications

(16 citation statements)

References 23 publications

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“…Studies of gene expression during BK viremia and BKN have shown upregulation of cytotoxic T cell as well as NK cell-associated transcripts (20). In contrast to the predominantly CD8+ T cell response observed in our study, other investigators have found the polyfunctional CD4+ T cell response to be upregulated during viral replication (21,22), which may be related to measurement of T cell function after resolution of viremia, as CD4+ has been shown to be associated with maintenance of viral control (13).…”

Section: Discussionmentioning

confidence: 99%

Increased Frequency of BK Virus-Specific Polyfunctional CD8+ T Cells Predict Successful Control of BK Viremia After Kidney Transplantation

Schaenman¹,

Korin

Sidwell

et al. 2017

Transplantation

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Background BK virus infection remains an important cause of loss of allograft function after kidney transplantation. We sought to determine whether polyfunctional T cells secreting multiple cytokines simultaneously, which have been shown to be associated with viral control, could be detected early after start of BK viremia, which would provide insight into the mechanism of successful antiviral control. Methods Peripheral blood mononuclear cells collected during episodes of BK viral replication were evaluated by multiparameter flow cytometry after stimulation by overlapping peptide pools of BK virus antigen to determine frequency of CD8+ and CD4+ T cells expressing 1 or more cytokines simultaneously, as well as markers of T cell activation, exhaustion, and maturation. Results BK virus controllers, defined as those with episodes of BK viremia of 3 months or less, had an 11-fold increase in frequency of CD8+ polyfunctional T cells expressing multiple cytokines, as compared with patients with prolonged episodes of BK viremia. Patients with only low level BK viremia expressed low frequencies of polyfunctional T cells. Polyfunctional T cells were predominantly of the effector memory maturation subtype and expressed the cytotoxicity marker CD107a. Conclusions Noninvasive techniques for immune assessment of peripheral blood can provide insight into the mechanism of control of BK virus replication and may allow for future patient risk stratification and customization of immune suppression at the onset of BK viremia. 5

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Section: Discussionmentioning

confidence: 99%

Increased Frequency of BK Virus-Specific Polyfunctional CD8+ T Cells Predict Successful Control of BK Viremia After Kidney Transplantation

Schaenman¹,

Korin

Sidwell

et al. 2017

Transplantation

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“…However, the evaluation using highthroughput microarray analysis of PVAN/TCMR tissue allograft samples to significantly enrich the genomic picture of these pathological features is scarce. Recently, Lubetzky et al 12 investigated the genomics of PVAN, mainly in whole blood and in a reduced number of tissue allograft samples by microarray analysis. Authors reported a significantly increased pathogenesis-based transcript activity of cytotoxic T cells and natural killer cells in PVAN resembling TCMR, suggesting the involvement of adaptive and innate immunity in both settings.…”

Section: Introductionmentioning

confidence: 99%

Intragraft Antiviral-Specific Gene Expression as a Distinctive Transcriptional Signature for Studies in Polyomavirus-Associated Nephropathy

et al. 2016

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Background Polyomavirus nephropathy (PVAN) is a common cause of kidney allograft dysfunction and loss. To identify PVAN-specific gene expression and underlying molecular mechanisms we analyzed kidney biopsies with and without PVAN. Methods The study included 168 posttransplant renal allograft biopsies (T cell mediated rejection=26, PVAN=10, normal functioning graft (STA) =73, and interstitial fibrosis/tubular atrophy (IF/TA) =59) from 168 unique kidney allograft recipients. We performed gene expression assays and bioinformatics analysis to identify a set of PVAN-specific genes. Validity and relevance of a subset of these genes are validated by QPCR and IHC. Results Unsupervised hierarchical clustering analysis of all the biopsies revealed high similarity between PVAN and TCMR gene expression. Increased statistical stringency identified 158 and 252 unique PVAN and TCMR injury-specific gene transcripts respectively. While TCMR-specific genes were overwhelmingly involved in immune response costimulation and TCR signaling, PVAN-specific genes were mainly related to DNA replication process, RNA polymerase assembly and pathogen recognition receptors. A principal component analysis using these genes further confirmed the most optimal separation between the 3 different clinical phenotypes. Validation of 4 PVAN-specific genes (RPS15, CFD, LTF, and NOSIP) by QPCR and confirmation by immunohistochemistry of 2 PVAN-specific proteins with anti-viral function (LTF and IFITM1) was done. Conclusions In conclusion, even though PVAN and TCMR kidney allografts share great similarities on gene perturbation, PVAN-specific genes were identified with well-known anti-viral properties that provide tools for discerning PVAN and AR as well as attractive targets for rational drug design.

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“…Additional evidence of T cell activation during viremia or PVAN includes the expression of mRNA associated with a cytotoxic program in T cells. 76 …”

Section: Immunology Of Pvanmentioning

confidence: 99%

“…There is an inflammatory response resembling histologically and genetically to acute rejection. 76,86 Whether this response is appropriate or is overwhelming, as an immune reconstitution syndrome, is not known. Two questions remain, does this process trigger fibrosis 87 and/or allospecific damage ?…”

Section: Immunology Of Pvanmentioning

confidence: 99%

“…76 Natural killer cell activity is controlled by opposing signals that come from a balance between activating and inhibitory receptors and can contribute to the orchestration of the adaptive immune response as well as mediating direct killing of infected cells. Many strategies are developed by viruses to avoid recognition by NK cells.…”

Section: Innate Immune Responsementioning

confidence: 99%

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BK Polyomavirus and the Transplanted Kidney

et al. 2016

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BK polyomavirus is ubiquitous, with a seropositivity rate of over 75% in the adult population. Primary infection is thought to occur in the respiratory tract, but asymptomatic BK virus latency is established in the urothelium. In immunocompromised host, the virus can reactivate but rarely compromises kidney function except in renal grafts, where it causes a tubulointerstitial inflammatory response similar to acute rejection. Restoring host immunity against the virus is the cornerstone of treatment. This review covers the virus-intrinsic features, the posttransplant microenvironment as well as the host immune factors that underlie the pathophysiology of polyomavirus-associated nephropathy. Current and promising therapeutic approaches to treat or prevent this complication are discussed in relation to the complex immunopathology of this condition.

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Genomics of BK Viremia in Kidney Transplant Recipients

Abstract: The results showed increased activity of cytotoxic T cells and natural killer cells in BKVN and viremia samples resembling acute rejection and suggested the involvement of both adaptive and innate immunity.

Cited by 20 publications

References 23 publications

Increased Frequency of BK Virus-Specific Polyfunctional CD8+ T Cells Predict Successful Control of BK Viremia After Kidney Transplantation

Increased Frequency of BK Virus-Specific Polyfunctional CD8+ T Cells Predict Successful Control of BK Viremia After Kidney Transplantation

Intragraft Antiviral-Specific Gene Expression as a Distinctive Transcriptional Signature for Studies in Polyomavirus-Associated Nephropathy

BK Polyomavirus and the Transplanted Kidney

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