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IFN-γ-induced iNOS expression in regulatory macrophages prolongs allograft graft survival in fully immunocompetent recipients.

ABSTRACT: Mouse monocytes exposed to M-CSF and IFN-γ were driven to a suppressor phenotype over a seven day culture period. The resulting regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarised macrophages and monocyte-derived DCs. M regs completely suppressed polyclonal T cell proliferation through an inducibile nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs were found to eliminate cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5x10^6 donor-strain M regs prior to transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c and C57BL/6-to-BALB/c strain combinations; this graft-protective effect was alloantigen-specific. M regs from Nos2-deficient mice did not prolong allograft survival, proving that M reg function in vivo is iNOS-mediated and dependent on living cells. Co-treatment with 1 mg/kg/day rapamycin for 10 days post-transplant markedly enhanced the effect of M regs. In untransplanted C57BL/6 recipients, M regs of BALB/c origin were detectable for up to 2 weeks post-infusion. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of tolerogenic macrophages, which resemble human M regs in their derivation, phenotype and in vitro functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE32690 | GEO | 2013/12/21

SECONDARY ACCESSION(S): PRJNA146905

REPOSITORIES: GEO

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IFN-M-NM-3-induced iNOS expression in regulatory macrophages prolongs allograft graft survival in fully immunocompetent recipients.

Project description:Mouse monocytes exposed to M-CSF and IFN-M-NM-3 were driven to a suppressor phenotype over a seven day culture period. The resulting regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarised macrophages and monocyte-derived DCs. M regs completely suppressed polyclonal T cell proliferation through an inducibile nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs were found to eliminate cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5x10^6 donor-strain M regs prior to transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c and C57BL/6-to-BALB/c strain combinations; this graft-protective effect was alloantigen-specific. M regs from Nos2-deficient mice did not prolong allograft survival, proving that M reg function in vivo is iNOS-mediated and dependent on living cells. Co-treatment with 1 mg/kg/day rapamycin for 10 days post-transplant markedly enhanced the effect of M regs. In untransplanted C57BL/6 recipients, M regs of BALB/c origin were detectable for up to 2 weeks post-infusion. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of tolerogenic macrophages, which resemble human M regs in their derivation, phenotype and in vitro functions. The dataset comprises 36 samples divided into twelve sample groups each representing a certain monocyte/macrophage subtype

2013-12-21 | E-GEOD-32690 | biostudies-arrayexpress

Preoperative Administration of Donor-derived Human M regs to Kidney Transplant Recipients (Agilent RISET 2.0)

Project description:Experiments in preclinical transplant models have indicated that preoperative administration of donor-derived M regs to transplant recipients may promote beneficial regulatory responses to a subsequent allograft. This contention is supported by results from the TAIC-I and –II clinical studies, which demonstrated that infusion of a crude cell preparation containing regulatory macrophages was both safe and could promote a state of donor-specific hyporesponsiveness. In an extension of this work, two patients were treated with donor-derived M regs prior to receiving a living-donor kidney transplant. Keywords: Classification of clinical samples

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Australian Chronic Allograft Dysfunction III

Project description:The Australian Chronic Allograft Dysfunction (AUSCAD) study is an ongoing single centre cohort study at Westmead hospital in Australia. In this section of the study, we aimed to identify biomarkers for allograft rejection in kidney transplant recipients, 3-months after their transplant. Our study recruited 123 patients, each having protocol renal allograft biopsies taken 3-months post transplantation.

2024-04-05 | GSE261892 | GEO

Quantitative proteome analysis of liver in acute cardiac rejection in mice

Project description:In order to study the changes of liver protein level in mice with acute cardiac rejection, we established a mouse model of ectopic heart transplantation. According to the matching relationship between recipient and donor, they were divided into the following two groups: allograft group (ALLO), BALB/ C hearts were transplanted into C57BL/6J recipients with complete mismatch of major histocompatibility complex; In the syngeneic transplantation group (ISO), C57BL/6J hearts were transplanted into MHC-matched C57BL/6J recipients. On day 6 after mouse heart transplantation, livers were obtained from recipient mice in the allograft group (n = 3) and from recipient mice in the syngeneic (ISO) group (n = 3). A series of techniques such as protein extraction, enzyme digestion, TMT labeling, HPLC classification, liquid chromatography-mass spectrometry tandem analysis, database search and bioinformation analysis were used to study the quantitative proteome of samples.

2022-09-05 | PXD044536 | iProX

Early introduction of oral paricalcitol in renal transplant recipients.

Project description:In stable renal transplant recipients with hyperparathyroidism, the vitamin D agonist paricalcitol reduces the level of proteinuria. Animal studies have indicated possible anti-fibrotic and anti-inflammatory effects of paricalcitol. We hypothesised that early introduction of paricalcitol in de novo renal transplant recipients would reduce proteinuria and counteract development of fibrosis in the allograft.

2017-09-01 | GSE83486 | GEO

Australian Chronic Allograft Dysfunction II

Project description:The Australian Chronic Allograft Dysfunction (AUSCAD) study is an ongoing single centre cohort study at Westmead hospital in Australia. In this section of the study, we aimed to identify biomarkers for chronic allograft dysfunction in kidney transplant recipients. Our study recruited 136 patients, each having protocol renal allograft biopsies taken pre transplantation.

2024-04-05 | GSE261240 | GEO

Mus musculus

Project description:IFN-γ-induced iNOS expression in regulatory macrophages prolongs allograft graft survival in fully immunocompetent recipients.

| PRJNA146905 | ENA

The Role of Macrophages in the Development of Human Renal Allograft Fibrosis in the First Year after Transplantation

Project description:The aim of this study was to investigate the role of infiltrating macrophages in renal allograft fibrosis. Forty-six protocol renal allograft biopsies obtained one-year after transplantation were stained with Sirius Red to quantify fibrosis and double stained with CD68 and CD206 to identify the proportion of alternately activated (M2) macrophages. 23 protocol biopsies obtained 12 months post transplant were analyzed for gene expression by microarray, which was correlated with macrophage infiltration and the severity of fibrosis. Phenotypic analysis showed 92% of infiltrating macrophages exhibited an M2 phenotype with CD68+CD206+ dual staining. Gene microarrays demonstrated a distinct alloimmune response despite the lack of rejection and inflammatory infiltrate with upregulation of interferon-γ-response genes. This suggests that following initiation of Th1 driven macrophage proliferation or infiltration, M2 macrophages contribute to tubular injury and progression of fibrosis. 23 protocol renal biopsies were obtained from patients at 12 month post transplant. The study population was divided into two groups according to the number of infiltrating macrophages (CD68 positive cells) (Group I: Recipients with a low number of infiltrating macrophages, CD68 positive cells < 400/mm2; Group II: Recipients with a high number of infiltrating macrophages, CD68 positive cells ≥ 400/mm2). Additional analyses were undertaken by dividing the group into those with fibrosis (ci score >1) and those without. To correlate gene expression with kidney fibrosis, or intensity of CD68 infiltrate, Spearman correlations analysis of the gene expression data with 12 month IFTA was performed and the correlation co-efficiency and its p value calculated. Gene Ontology enrichment and IPA pathway and network analysis (Ingenuity System Inc.) were performed on the associated genes. All p-values were two-sided, and p < 0.05 was considered significant.

2015-01-28 | E-GEOD-65326 | biostudies-arrayexpress

MOLECULAR CHARACTERIZATION OF LIVER ALLOGRAFTS FROM OPERATIONALLY TOLERANT TRANSPLANT RECIPIENTS (Illumina)

Project description:In clinical organ transplantation complete cessation of immunosuppressive therapy can be successfully accomplished in selected recipients providing a proof-of-principle that allograft tolerance is attainable in humans. The intra-graft molecular pathways associated with human allograft tolerance, however, have not been comprehensively studied before. In this study we analyzed sequential liver tissue samples collected from liver recipients enrolled in a prospective multicenter immunosuppressive withdrawal clinical trial. Tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis.These results point to a critical role of iron homeostasis in the regulation of intra-graft alloimmune responses in humans and provide a set of novel biomarkers to conduct drug-weaning trials in liver transplantation. The complete database comprised the expression measurements of 48766 probes in liver biopsies. The liver biopsy specimens available for the study were obtained: a) before immunosuppressive drugs were discontinued from tolerant (TOL, n=24) and non-tolerant (Non-TOL, n=29) recipients; b) at the time of rejection from non-tolerant recipients (Non TOL REJ, n=18); In addition, liver tissue samples were also collected from the following control patient groups: a) liver transplant recipients with chronic hepatitis due to recurrent hepatitis C virus infection (HEPC, n=12); b) liver transplant recipients with typical acute cellular rejection taking place during the immediate post-transplant period (REJ, n=9); c) liver transplant recipients under maintenance immunosuppression with normal liver function and normal liver histology 1 year after transplantation (CONT-Tx, n=8); and d) non-transplanted patients undergoing surgery for colorectal liver metastases (CONT, n=10).

2012-01-09 | E-GEOD-26625 | biostudies-arrayexpress

Profiling circulating microRNA expression in a mouse model of nerve allotransplantation (part 2)

Project description:Background. The lack of noninvasive biomarkers of rejection remains a challenge in the accurate monitoring of deeply buried nerve allografts and precludes optimization of therapeutic intervention. This study aimed to establish the expression profile of circulating microRNAs (miRNAs) during nerve allotransplantation with or without immunosuppression. Methods. Balb/c mice were randomized into 3 experimental groups, that is, (1) untreated isograft (Balb/c → Balb/c), (2) untreated allograft (C57BL/6 → Balb/c), and (3) allograft (C57BL/6 → Balb/c) with FK506 immunosuppression. A 1-cm Balb/c or C57BL/6 donor sciatic nerve graft was transplanted into sciatic nerve gaps created in recipient mice. At 1, 3, 7, 10, and 14 d after nerve transplantation, nerve grafts, whole blood, and sera were obtained for miRNA expression analysis with an miRNA array and subsequent validation with quantitative PCR.

2014-07-01 | GSE48971 | GEO

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