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Kidney gene expression profile following the transplant-induced reactivation of MCMV

ABSTRACT: Reactivation of latent HCMV is a significant infectious complication of organ transplantation, and current therapies target viral replication once reactivation of transcriptionally silent, latent virus has already occurred. The specific molecular pathways that activate viral gene expression are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. MCMV is a valuable model for studying latency and reactivation of CMV induced by organ transplantation. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces transcriptional reactivation of immediate early (IE) gene expression within 48 hr. We used microarrays to profile global mouse kidney gene expression associated with transcriptional reactivation of MCMV immediate early gene expression at 48 hr after transplant of MCMV latently infected kidneys into allogeneic recipients. We identified differentially expressed genes and pathways associated with both early acute rejection and reactivation of MCMV.

ORGANISM(S): Mus musculus

PROVIDER: GSE72392 | GEO | 2015/08/27

SECONDARY ACCESSION(S): PRJNA293941

REPOSITORIES: GEO

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Project description:The frequency of delayed function of kidney transplants varies greatly and is associated with the quality of graft, donor age, and the duration of cold ischemia time. Body weight differences between donor and recipient can affect primary graft function. The underlying mechanism is poorly understood. Here, we have transplanted kidney grafts from commensurate body weight (L-WD) or reduced body weight (H-WD) donor rats into syngeneic or allogeneic recipients. 24 hours post-transplantation, serum creatinine level in H-WD recipients was significantly higher compared to that of L-WD recipients indicating impaired primary graft function. We detected a 10 fold higher transcription of IL-6 and dramatically increased tubular destruction in grafts from H-WD recipients. This was accompanied by decreased expression of genes associated with kidney function and an up-regulation of other genes such as cytochrome P450 isoforms, FosL and Trib3 as revealed by DNA microarray analysis. A single application of IL-6 into L-WD recipients is sufficient to impair primary graft function and to cause tubular damage. Whereas, immediate neutralization of IL-6 receptor signaling rescued primary graft function resulting in low serum creatinine levels, well-preserved kidney graft architecture and a normalized gene expression profile. These findings have strong clinical implication as anti-IL6R treatment of patients receiving grafts from lower-weight donors could be used to improve primary graft function. The dataset comprises eight samples divided into four sample groups. Each group represents rat kidneys collected after allogeneic transplantation under a certain condition and includes two biological replicates. The first group is characterized by a high body weight difference between donor and recipient, rats in the second group exhibit a low weight difference. Group three and four are similar to group one, but underwent an additional treatment with anti-IL6R mAb or prednisolone immediately after transplantation.

Project description:Microarray analyses provide a powerful approach to identify gene expression alterations following kidney transplantation. However, the heterogeneity of human kidney transplant specimens and the variation in sample preparation precludes conclusions regarding the underlying mechanisms of the observed alterations. We used a well defined experimental rat kidney transplantation model with consistent transplant and sample preparation procedures to analyze genome wide changes in gene expression after syngeneic (sTX) and allogeneic transplantation (aTX) four days after transplantation. Both interventions were associated with dramatic changes in gene expression. Genes and Pathways related to immune response were extremely up regulated after aTX. Several of the up regulated genes have been described by other groups and we are able to proof this in one study. But several genes are reported for the first time to be up regulated in expression after renal aTX. The function of these genes in acute rejection process has to be evaluated. On the other hand the up regulation of regulatory or protective genes indicates that regulatory mechanism are activated after aTX trying to down regulate the immune response or protect the tissue against the immune system. The study is capable to serve as a representative study in aTX mediated gene expression by covering the known transcriptional changes reported by other groups and identification of novel markers and pathways. Further analysis of the duplicated datasets by other groups can help for a better understanding of the mechanisms mediated by acute rejection and thereby increase the therapeutic threatment. Experiment Overall Design: Male LewisâBrown-Norway (LBN) and Lewis (LEW) rats were used in the present study. All recipients were bilaterally nephrectomized immediately before donor kidney TX. In brief, the left kidney including ureter, renal artery, a piece of aorta and renal vein was transplanted into the recipient. For the allogeneic TX (aTX) model, kidneys of LBN-rats (n=5) were transplanted into LEW-rats and for the syngeneic TX (sTX) model kidneys from LBN-rats (n=5) were transplanted into LBN-rats. The LBN-into-Lewis model leads to marked histological changes typical for acute transplant rejection. The second kidney of the LBN-donors (n=5) served as controls.

Project description:Reconstitution of cytomegalovirus (CMV)-specific immunity following transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Due to the persistence of CMV, most CMV-specific CD8+ T cells become terminally differentiated effector cells (TEFF). However, a minor subset retains a memory phenotype (TM). Interestingly, recent studies suggest that CMV-specific CD8+ T cells with different phenotypes may have different abilities to reconstitute sustained immunity following transfer. The immunology of human CMV (HCMV) infections is reflected in the mouse model of MCMV infection. We found that HCMV- and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. After transfer, the proliferative capacity of MCMV-specific TM cells was vastly superior to TEFF cells. Strikingly, TM cells expanded and established sustained and diverse T cell populations even after multiple challenges. Although both TEFF and TM cells could protect Rag-/- mice, only TM cells could consistently survive after transfer into immune replete, latently infected recipients and respond if recipient immunity was lost. These data show that CMV-specific TM cells retain memory function during persistent infection and can re-establish CMV immunity when necessary. C57BL/6 mice were infected intraperitoneally (i.p.) with MCMV strain MW97.01 between 6-16 weeks of age. Splenocytes were isolated from chronically-infected mice and co-stained with three PE-conjugated tetramers loaded with the antigenic peptides from M38, m139 and IE3, all of which promote memory inflation. Cells were then stained with fluorescently conjugated antibodies and sorted on a MoFlo cell sorter. Naïve CD8+ cells were identified as CD44lo. MCMV-specific T cells were identified as CD8+, CD44hi and tetramer binding and then further segregated into memory and effector cells subsets by their expression of KLRG1 and CD127.

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Kidney gene expression profile following the transplant-induced reactivation of MCMV

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