Persistent cytomegalovirus infection in kidney allografts is associated with inferior graft function and survival

Helanterä, Ilkka; Koskinen, Petri; Finne, Patrik; Loginov, Raisa; Kyllönen, L.; Salmela, K.; Grönhagen‐Riska, Carola; Lautenschlager, Irmeli

doi:10.1111/j.1432-2277.2006.00364.x

Cited by 72 publications

(56 citation statements)

References 22 publications

(35 reference statements)

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“…35 gd T-cell ADCC could represent a new physiopathologic contribution to the well known but poorly understood association between CMV infection and the increased occurrence of rejection, 20,51 poor long-term graft function, 21,[52][53][54] and low graft survival. 55,56 Hence, both CMV and DSA are required to see a correlation between circulating gd T cells and graft function deterioration, consistent with a model where CMV infection evokes activation and expansion of CD16 pos gd T cells in undetermined anatomic sites, and DSA triggers their ADCC function within graft microcirculation. This implication of gd T cells in graft rejection seemingly contrasts with the previously reported Vd1 T-cell expansion in the peripheral blood and grafts of operationally tolerant liver transplant recipients.…”

Section: Discussionsupporting

confidence: 73%

Cytomegalovirus-Responsive γδ T Cells

Bachelet

Couzi

Pitard

et al. 2014

Journal of the American Society of Nephrology

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Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large gd T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive gd T cells express the Fcgreceptor CD16, suggesting that gd T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16 pos gd T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating gd T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced gd T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced gd T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.

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Section: Discussionsupporting

confidence: 73%

Cytomegalovirus-Responsive γδ T Cells

Bachelet

Couzi

Pitard

et al. 2014

Journal of the American Society of Nephrology

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“…Immunosuppression upsets this balance, permitting the virus to escape the clearance mechanisms of the host. In both acute (51) and likely chronic graft dysfunction (52), CMV disease primarily involves the activation of cell-mediated immunity and is associated with inflammation and fibrosis in the graft.…”

Section: Balance Of Host-virus Interactions and Immunosuppressionmentioning

confidence: 99%

Viral Subversion Mechanisms in Chronic Kidney Disease Pathogenesis

Bruggeman

2007

Clinical Journal of the American Society of Nephrology

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Viruses cannot autonomously replicate but must rely on the host cellular machinery to support their life cycle. Through natural selection, viruses have evolved strategies to co-opt the host organism to be a better site for their propagation. Some of these strategies are directed at the cellular machinery and involve complicated and ingenious solutions to optimize infection, replication, viral gene expression, and new virion assembly and shedding. Other strategies are directed at the host's innate and adaptive immune systems that permit the virus to evade clearance mechanisms. The more common pathogenic viral infections in nephrology-cytomegalovirus, HIV-1, hepatitis C virus, polyomavirus BK, and parvovirus B19 -all have acquired subversion strategies that benefit the virus but because they interfere with normal cellular and immune processes also have become pathogenic to the host. In addition, the highly prevalent viruses cytomegalovirus, BK, and B19 cause severe disease only in the setting of immunosuppression, revealing the very delicate balance that some viruses have achieved with their host's immune system. Thus, selective pressure for survival drives both the evolution of more sophisticated viruses and the host immune system as it evolves to combat the environment of adapting and emerging infectious agents. Understanding the molecular mechanisms of these viral subversion strategies may reveal new targets for the development of highly specific antiviral therapies and also aid vaccine development.

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“…[15][16][17][18] Previous studies analyzing Figure 5. hCMV inhibits constitutive HIF2a mRNA expression in HEPCs.…”

Section: Discussionmentioning

confidence: 99%

“…13 The kidney is a target organ for hCMV, and human kidney cells of glomerular, vascular, and tubular origin are susceptible to infection in vitro. 14 hCMV DNA and proteins can be detected in renal allografts, [15][16][17][18] and infection has been associated with severe anemia 6 months after renal transplantation. 19 To our knowledge, no studies have detailed its presence or absence in CKD kidneys.…”

mentioning

confidence: 99%

Human Cytomegalovirus Inhibits Erythropoietin Production

Butler

Džabić

Bakker

et al. 2014

Journal of the American Society of Nephrology

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Anemia is a feature of CKD and a complication of renal transplantation, often caused by impaired production of erythropoietin. The kidney is a target organ for human cytomegalovirus (hCMV) in such patients, but it is not known whether hCMV effects erythropoietin production. We found that kidneys from patients with CKD were positive for hCMV protein and that blood levels of hCMV IgG inversely correlated with red blood cell count. In mice, systemic murine cytomegalovirus infection decreased serum erythropoietin levels. In human erythropoietin-producing cells, hCMV inhibited hypoxia-induced expression of erythropoietin mRNA and protein. hCMV early gene expression was responsible, as ultravioletinactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxiainducible transcription factor (HIF)-1a and HIF2a, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2a mRNA. HIF2a is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2a was inhibited in hCMV-infected cells, and the extent of inhibition correlated with hCMV protein expression. Our findings suggest that renal hCMV infection could induce or exacerbate anemia in patients. 25: 166925: -167825: , 201425: . doi: 10.1681 Anemia is a frequent feature of CKD and a common complication of renal transplantation. Large cohort studies have shown that around 40% of patients develop anemia following transplant surgery. 1-4 Interestingly, the incidence of anemia is unexpectedly high in patients with an otherwise functioning renal transplant (for review, see Vanrenterghem 5 ). Most evidence to date suggests that impaired erythropoietin (EPO) production by the renal allograft is the most common cause of post-transplant anemia. 5 In patients with CKD, as renal function decreases the incidence of anemia increases, to .70% in patients with CKD stage 5. Although its cause is multifactorial, a significant factor is inadequate production of EPO. The mechanisms behind the impaired renal EPO production remain to be elucidated. 6 EPO is a glycoprotein hormone, produced primarily in the kidney, that controls erythropoiesis and regulates hematocrit. 7 Treatment with recombinant EPO can correct post-transplant and renal diseaseassociated anemia, 8 although the cause of EPO loss is unknown. In adults, EPO originates mainly from fibroblast-type cells in the renal cortex 9 and is controlled by heterodimeric (a/b) hypoxia-inducible transcription (HIF) factors. Under normoxic conditions, HIFa subunits (HIF1a and HIF2a) are constitutively produced but are subject to rapid proteasomal degradation by the von Hippel-Lindau tumor suppressor, the recognition complex of an E3 ubiquitin J Am Soc Nephrol

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Persistent cytomegalovirus infection in kidney allografts is associated with inferior graft function and survival

Cited by 72 publications

References 22 publications

Cytomegalovirus-Responsive γδ T Cells

Cytomegalovirus-Responsive γδ T Cells

Viral Subversion Mechanisms in Chronic Kidney Disease Pathogenesis

Human Cytomegalovirus Inhibits Erythropoietin Production

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