Macrophage infiltration induced by donor hypovolemia protects against severe primary graft dysfunction in mouse lung transplantation
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PROVIDER: PRJNA657514 | ENA |
REPOSITORIES: ENA
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Project description:BACKGROUND: Hypovolemia is common in lung donors before or after brain death. However, its impact on primary graft function (PGD) remains obscure. METHODS: A clinically relevant two-hit model of PGD was established by integrating hypovolemic shock (HS) and cold ischemia-reperfusion in a mouse model of orthotopic lung transplantation (LTx) from C57BL/6 to Balb/c. At -48 hours, HS was induced to donor by withdrawal of blood from femoral artery and keeping the mean arterial pressure at 15±5 mmHg for 4 h. At -24 hours, donor lungs were retrieved from mice with or without HS and stored at 0ºC until transplantation. CD11b-DTR mice were used as donor and treated with Diphtheria Toxin (DT) to deplete graft-infiltrating macrophages. RESULTS: HS mainly caused macrophage-predominant infiltration around pulmonary artery injury systemic inflammatory response, but little impairment of lung function even if in combination with cold ischemia-reperfusion. Transcriptional profiling showed HS pretreatment increased pulmonary damage and alveolar remodeling but ameliorated inflammatory infiltration when compared to one-hit model of 12 hours cold ischemia-reperfusion injury. The allografts with donor DT-treatment one day ahead of HS showed injury and dysfunction at donation and worsened further at 24 hours reperfusion, whereas the allografts with recipient DT-treatment immediately after transplantation showed similar function and histology to the control treated with saline. CONCLUSION: Donor hypovolemia causes pulmonary artery injury and infiltration but has little impact on allograft function, even in combination with 24 h cold ischemia. Graft-infiltrating macrophages are critical in protecting graft from HS-induced injury and cold ischemia-reperfusion injury.
2022-03-30 | GSE156322 | GEO
Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study Matched case-control observational study: 10 primary graft dysfunction cases vs 16 Good outcome cases. One replicate per array.
2008-09-15 | E-GEOD-9102 | biostudies-arrayexpress
Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study
2008-09-15 | GSE9102 | GEO
Project description:Donor organ shortage, growing waiting lists and organ discard rates are key problems in kidney transplantation. Donor organ quality is a critical factor determining post-transplant graft outcomes. However, organ quality is difficult to predict. Balancing the use of marginal donors without affecting outcomes is a main issue in the transplant field. The decision of acceptance of a kidney organ for transplantation is mainly based on donor organ biopsy findings, even though there are recognized limitations. The lack of better measures of organ quality at the time of transplantation as a predictor of performance graft outcome is a serious clinical challenge. Herein, we propose the use of a limited set of genes that captures intrinsic biology of kidney donor organs to improve available scoring systems. We studied gene expression in 192 deceased donor kidney biopsies and evaluated short-term outcomes which included delayed graft function and eGFR (high versus low) at 24 months for 168 kidney transplant recipients.
2022-06-13 | GSE147451 | GEO
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.
2010-04-08 | E-GEOD-15813 | biostudies-arrayexpress
Project description:The significance of borderline changes (BL) in kidney allograft biopsies is widely debated. We examined differences in gene expression patterns between early clinical biopsy tissue and 3-month protocol biopsy tissue, all of which had histological BL changes and identified specific molecular BL patterns associated with poor graft outcome. The expression profiles were analyzed in training set of patients and next data were validated in validation cohort using RT-qPCR. Using the Illumina microarray technology, we observed greater expression of immunity- and inflammation-related genes in tissues from early clinical biopsies compared to 3-month protocol biopsies with BL findings. In tissues with early clinically manifested BL changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes, specifically with higher donor age and expression of macrophage receptor CLEC5A. In the 3-month protocol biopsies with BL changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. This study highlights the molecular differences between clinical and subclinical biopsies with similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those who received grafts from expanded criteria donors (ECDs). The experiments were performed with total RNA derived from the renal graft biopsy samples of 28 different patients who had undergone a kidney transplantation. Only the patients with diagnosis of borderline changes early (M-bM-^IM-$2 months) or protocolar (3 months) were included in the study. RNA profiles of patients with stable and deteriorated graft function during 2 years after transplantation were compared. As microarray platform, Illumina HumanHT-12 v4.0 Expression BeadChips (Illumina) was used. The chip scanning was performed with a BeadStation 500 instrument (Illumina Inc), and the raw data were extracted with the BeadStudio Data Analysis Software (Illumina). The R software lumi package was used to further process the raw data. The quantile method was used for normalization.
2013-12-19 | E-GEOD-52694 | biostudies-arrayexpress
Project description:Analysis of donor CD4+ and CD8+ T cells purified from spleens and ovaries after murine syngeneic and allogeneic hematopoietic stem cell transplantation Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). While the role of pretransplant conditioning regimen has been well appreciated, increasing application of reduced-intensity conditioning facilitated us to revisit the other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. To study transcriptomes of donor T cells infiltrating into the ovary, donor T cells were sorted from recipients' ovaries and microarray analysis was performed.
2017-05-12 | GSE81397 | GEO
Project description:To assess if gene expression signatures could predict acute graft-versus-host disease, we examined the global gene expression profiles of peripheral blood mononuclear cells at day +14 post-transplantation from 94 patients undergoing allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.
2010-06-09 | E-MEXP-1824 | biostudies-arrayexpress
Project description:Primary graft dysfunction (PGD) is the leading cause of early mortality after lung transplantation. Anti-collagen type-V (col(V)) immunity has been observed in animal models of ischemia-reperfusion injury (IRI) and in PGD. We hypothesized that collagen type-V is an innate danger signal contributing to PGD pathogenesis. Methods: Anti-col(V) antibody production was detected by flow cytometric assay following cultures of murine CD19+ splenic cells with col(V). Responding murine B cells were phenotyped using surface markers. RNA-Seq analysis was performed on murine CD19+ cells. Levels of anti-col(V) antibodies were measured in 188 recipients from the Lung Transplant Outcomes Group (LTOG) after transplantation. Results: Col(V) induced rapid production of anti-col(V) antibodies from murine CD19+ B cells. Subtype analysis demonstrated innate B-1 B cells bound col(V). Col(V) induced a specific transcriptional signature in CD19+ B cells with similarities to, yet distinct from, B cell receptor (BCR) stimulation. Rapid de novo production of anti-col(V) Abs was associated with an increased incidence of clinical PGD after lung transplant. Conclusions: This study demonstrated that col(V) is an rapidly recognized by B cells and has specific transcriptional signature. In lung transplants recipients the rapid seroconversion to anti-col(V) Ab is linked to increased risk of grade 3 PGD.
2019-11-20 | GSE140681 | GEO
Project description:Delayed graft function (DGF) is associated with a reduced graft survival. 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. We prospectively enrolled 932 kidney graft recipients from 466 donors. A total of 226 recipients experienced DGF. Among the 466 donors, in 290 both recipients presented with early graft function (EGF, group A), in 50 both recipients experienced DGF (group B) and in 126 one recipient presented with DGF and the other with EGF (group C). In group C we randomly selected 7 couples of DGF/EGF recipients. In these patients, circulating mononuclear cells were harvested before transplantation and their transcriptomic profile was investigated by a microarray approach. Results were validated by qPCR in an independent group of EGF/DGF couples.
2022-12-22 | E-MTAB-10747 | biostudies-arrayexpress