Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Molecular characterization of chronic antibody mediated rejection in kidney transplantation (mRNA CD4)

ABSTRACT: Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. We performed microarray experiments in CD4+ T cells isolated from a small independent group of 5 patients included into the control-group and 5 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

ORGANISM(S): Homo sapiens

SUBMITTER: Paola Pontrelli

PROVIDER: E-GEOD-64261 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation.

Rascio Federica F Pontrelli Paola P Accetturo Matteo M Oranger Annarita A Gigante Margherita M Castellano Giuseppe G Gigante Maddalena M Zito Anna A Zaza Gianluigi G Lupo Antonio A Ranieri Elena E Stallone Giovanni G Gesualdo Loreto L Grandaliano Giuseppe G

The Journal of pathology 20150604 1

Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transpl ...[more]

PMID: 25925804

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Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 5 patients included into the control-group and 4 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 8 patients included into the control-group and 10 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

Project description:Delayed graft function (DGF) is associated with a reduced long-term graft survival. Ischemia-reperfusion damage and donors' features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the role of recipients' characteristics in the development of DGF to discover early genomics biomarkers in peripheral blood mononuclear cells (PBMC) in order to identify patients at risk. We prospectively enrolled 932 kidney graft recipients from 466 donors for both kidneys. A total of 226 recipients experienced DGF. Among the 466 donors, 290 couples of recipients both patients presented with early graft function (EGF, group A), 50 couples experienced DGF (group B) and 126 couples of recipients were discordant as one presented DGF and the other promptly recovered graft function (group C). In group C we randomly selected 10 couples of DGF/EGF recipients. Peripheral blood mononuclear cells (PBMC) were harvested before transplantation; their transcriptomic profile was investigated by a microarray approach and microarray results were validated by qPCR in an independent group (DGF n=25; EGF n=25). In the whole study group, DGF was independently associated with both donors’ and recipient’s features. Moreover, group A, B and C presented significant differences in both donors’ and recipients’ characteristics. In group C of patients, DGF was significantly associated with body mass index, dialysis modality and number of mismatches. Two-hundred and seventy-three genes were differentially expressed before transplantation in discordant EGF/DGF patients of group C. Their main biological functions were immune dysfunction and inflammation. Among the differentially expressed genes, we observed a significant increase in the expression of CCR2, the MCP-1 receptor, in DGF patients. CCR-2 and MCP-1 up-regulation was confirmed in an independent cohort of patients. Our results suggest that recipients' clinical and immunological features, potentially modulated by dialysis modality, are associated with the development of DGF independently of donors' features.

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:We previously observed reduced graft survival for kidney transplants having interstitial fibrosis with subclinical inflammation, but not fibrosis alone, on 1-year protocol biopsy. The current study aimed to determine whether fibrosis with inflammation at 1 year is associated with renal functional decline in a low-risk transplant cohort and to characterize the nature of the inflammation. Subjects were living-donor, tacrolimus/mycophenolate-treated transplant recipients without overt risk factors for reduced graft survival (n=151). Transplants with normal histology (n=86) or fibrosis alone (n=45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, while those having fibrosis with inflammation (n=20) had declining glomerular filtration rate and reduced graft survival. Immunohistochemistry confirmed increased interstitial T-cells and macrophages/dendritic cells in the fibrosis with inflammation group. Gene expression was performed on a subset of biopsies in each group and demonstrated increased expression of transcripts related to innate and cognate immunity in transplants having fibrosis with inflammation. Pathway- and pathological process-specific analyses of microarray profiles revealed that, in fibrosis with inflammation, over-expressed transcripts were enriched for potentially damaging immunological activities including Toll-like receptor signaling, antigen presentation/dendritic cell maturation, interferon gamma-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes. Thus, fibrosis with inflammation in 1-year protocol biopsies is associated with reduced graft survival and function and with a rejection-like gene expression signature even in recipients with no clinical risk for inferior outcome. Early interventions aimed at altering rejection-like inflammation may favor improved long-term KTx survival. We analyzed gene expression from a group of 65 renal transplant recipients. Patient groups were carefully selected to include patients on the same immunosuppression (Prograf-MMF-Pred), transplant type (LD), absence of over post-transplant complications (AR, BK, DGF). For each patient a 1 year protocol biopsy was examined by conventional histology and gene expression. By histology the patients were categorized as histologically normal (n=25, i/cg/ci=0), IF/TA (n=24, i/cg=0, ci>0) and IFTA+i (n=16, cg=0, i/ci>0). This dataset is part of the TransQST collection.

Dataset Information

Molecular characterization of chronic antibody mediated rejection in kidney transplantation (mRNA CD4)

Publications

A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation.

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