A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

Zhang, Zheng Jenny; Qiu, Longhui; Yan, Shi; Wang, Jiao Jing; Thomas, Paul M.; Kandpal, Manoj; Zhao, Lihui; Iovane, André; Liu, Xuefeng; Thorp, Edward B.; Chen, Qing Ching; Hummel, Mary; Kanwar, Yashpal S.; Abécassis, Michaël

doi:10.1111/ajt.15376

Cited by 26 publications

(50 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More related to our work is a parent-into-F1 model of allogeneic HCT in which chronic GvHD at > 100 days after HCT was found to be associated with an impaired antigen-specific antiviral immune response that was characterized by impaired tissue homing of antigenspecific T cells (Hossain et al, 2007). Besides a discussed mutual exacerbation of disease severity, evidence has been provided for a role of GvH and HvG responses in increasing the incidence of CMV reactivation from latency (Söderberg-Nauclér et al, 1997;Zhang et al, 2019).…”

Section: Discussionmentioning

confidence: 76%

Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation

Holtappels

Schader

Oettel

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Reactivation of latent cytomegalovirus (CMV) poses a clinical problem in transiently immunocompromised recipients of hematopoietic cell (HC) transplantation (HCT) by viral histopathology that results in multiple organ manifestations. Compared to autologous HCT and to syngeneic HCT performed with identical twins as HC donor and recipient, lethal outcome of CMV infection is more frequent in allogeneic HCT with MHC/HLA or minor histocompatibility loci mismatch between donor and recipient.It is an open question if a graft-vs.-host (GvH) reaction exacerbates CMV disease, or if CMV exacerbates GvH disease (GvHD), or if interference is mutual. Here we have used a mouse model of experimental HCT and murine CMV (mCMV) infection with an MHC class-I mismatch by gene deletion, so that either HCT donor or recipient lack a single MHC class-I molecule, specifically H-2 L d . This particular immunogenetic disparity has the additional advantage that it allows to experimentally separate GvH reaction of donor-derived T cells against recipient's tissues from host-vs.-graft (HvG) reaction of residual recipient-derived T cells against the transplanted HC and their progeny. While in HvG-HCT with L d -plus donors and L d -minus recipients almost all infected recipients were found to control the infection and survived, almost all infected recipients died of uncontrolled virus replication and consequent multiple-organ viral histopathology in case of GvH-HCT with L d -minus donors and L d -plus recipients. Unexpectedly, although anti-L d -reactive CD8 + T cells were detected, mortality was not found to be associated with GvHD histopathology. By comparing HvG-HCT and GvH-HCT, investigation into the mechanism revealed an inefficient reconstitution of antiviral high-avidity CD8 + T cells, associated with lack of formation of protective nodular inflammatory foci (NIF) in host tissue, selectively in GvH-HCT. Most notably, mice infected with an immune evasion gene deletion mutant of mCMV survived under otherwise identical GvH-HCT conditions. Survival was associated with enhanced antigen presentation and formation of protective NIF by antiviral CD8 + T Holtappels et al.Inefficient Antiviral Control After Allogeneic-HCT cells that control the infection and prevent viral histopathology. This is an impressive example of lethal viral disease in HCT recipients based on a failure of the immune control of CMV infection due to viral immune evasion in concert with an MHC class-I mismatch.

show abstract

Section: Discussionmentioning

confidence: 76%

Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation

Holtappels

Schader

Oettel

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…In conclusion, adoptive immunotherapy of CMV infection in HCT recipients with virus-specific CD8 + T cells not only prevents CMV organ disease but also ensures successful engraftment of the hematopoietic transplant in the BM stroma of CMV-infected HCT recipients. As a research perspective, we propose that in the murine SOT model of kidney transplantation (Zhang et al, 2019), adoptive immunotherapy with antiviral CD8 + T cells will not prevent mCMV reactivation from a latently-infected kidney transplant but likely will prevent subsequent virus dissemination to recipient's organs, as already suggested by promising clinical data (Roemhild and Reinke, 2016).…”

Section: Cmv-associated Inhibition Of Hematopoiesis Is Preventable Bymentioning

confidence: 98%

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Renzaho

Podlech

Kühnapfel

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Reactivation of latent cytomegalovirus (CMV) in recipients of hematopoietic cell transplantation (HCT) not only results in severe organ manifestations, but can also cause "graft failure" resulting in bone marrow (BM) aplasia. This inhibition of hematopoietic stem and progenitor cell engraftment is a manifestation of CMV infection that is long known in clinical hematology as "myelosuppression." Previous studies in a murine model of sex-chromosome mismatched but otherwise syngeneic HCT and infection with murine CMV have shown that transplanted hematopoietic cells (HC) initially home to the BM stroma of recipients but then fail to further divide and differentiate. Data from this model were in line with the hypothesis that infection of stromal cells, which constitute "hematopoietic niches" where hematopoiesis takes place, causes a local deficiency in essential hematopoietins. Based on this understanding, one must postulate that preventing infection of stromal cells should restore the stroma's capacity to support hematopoiesis. Adoptively-transferred antiviral CD8 + T cells prevent lethal CMV disease by controlling viral spread and histopathology in vital organs, such as liver and lungs. It remained to be tested, however, if they can also prevent infection of the BM stroma and thus allow for successful HC engraftment. Here we demonstrate that antiviral CD8 + T cells control stromal infection. By tracking male donor-derived sry + HC in the BM of infected female sry − recipients, we show the CD8 + T cells allow for successful donor HC engraftment and thereby prevent CMV-associated BM aplasia. These data provide a further argument for cytoimmunotherapy of CMV infection after HCT.

show abstract

“…Liver ischemia-reperfusion injury (IRI) poses a universal risk of adverse clinical outcomes in extended liver resections and orthotopic liver transplantation (OLT). The development of hepatic IRI after OLT has been associated with perioperative complications, including post-reperfusion syndrome, delayed graft, and primary non-function as well as acute rejection [1,2].…”

Section: Introductionmentioning

confidence: 99%

Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications

Czigány

Lurje

Schmelzle

et al. 2020

JCM

View full text Add to dashboard Cite

Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP—which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion—will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.

show abstract

A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

Cited by 26 publications

References 58 publications

Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation

Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications

Contact Info

Product

Resources

About