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A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice.

ABSTRACT: BACKGROUND STAT1/4 has been suggested to be involved in cardiac allograft rejection. However, no direct evidence regarding STAT3 has been established in cardiac allograft rejection. Here, we hypothesized that inhibition of STAT3 attenuates cardiac allograft rejection. MATERIAL AND METHODS To test our hypothesis, homotopic mouse heart transplantation was carried out in syngeneic C57BL/6 to C57BL/6 strain mice with or without oral gavage with NSC 74859, an inhibitor of STAT3. The immune response was investigated using real-time PCR for CD4 and CD8 surface makers of T cells and CD14 of monocytes and cytokines, including IL-2, IL-15, and IL-6 of allografts at 3, 6, and 9 days after transplantation. Prognosis was also evaluated. RESULTS We found that allografts with oral gavage of NSC 74859 whose CD4, CD8 T, and CD14 monocytes were significantly lower than that of allograft without oral gavage of NSC 74859, and the same was true for the expression of IL-2, IL-15, and IL-6. Immunohistochemical analysis of grafts showed reduced infiltration of monocytes/macrophages into the graft myocardium. Survival was also markedly extended in the NSC 74859 group. CONCLUSIONS Inhibition of IL-6/STAT3 using NSC 74859 was shown to remarkably alleviate cardiac allograft rejection in mice, indicating that the target against IL-6/STAT3 pathway might be clinically used as an alternative therapy for cardiac allograft rejection.

SUBMITTER: Lai Y

PROVIDER: S-EPMC6248023 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice.

Lai Yiquan Y Kuang Feng F Shan Zhonggui Z Liu Huaqing H

Annals of transplantation 20171103

BACKGROUND STAT1/4 has been suggested to be involved in cardiac allograft rejection. However, no direct evidence regarding STAT3 has been established in cardiac allograft rejection. Here, we hypothesized that inhibition of STAT3 attenuates cardiac allograft rejection. MATERIAL AND METHODS To test our hypothesis, homotopic mouse heart transplantation was carried out in syngeneic C57BL/6 to C57BL/6 strain mice with or without oral gavage with NSC 74859, an inhibitor of STAT3. The immune response w ...[more]

PMID: 29097651

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Project description:Low levels of plasma adiponectin, an adipocytokine that possesses anti-inflammatory and antiatherogenic properties, frequently observed among obese subjects correlate with higher prevalence of several cardiovascular diseases. This study investigated whether adiponectin modulates allograft rejection in major histocompatibility complex class II-mismatched cardiac transplants.We heterotopically transplanted Bm12 allografts into adiponectin-deficient (APN-/-, C57BL/6 background) or wild-type (APN+/+) mice. Some APN-/- mice received adiponectin reconstitution by adenovirus. Histologic analyses assessed allograft rejection, and real-time reverse-transcriptase polymerase chain reaction evaluated the genes for cytokines/chemokines associated with the immune and inflammatory responses. In addition, we tested the effect of adiponectin on proliferation and cytokine/chemokine production in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.Allografts transplanted to APN-/- mice showed severe acute rejection relative to transplants in APN+/+ hosts accompanied by increased accumulation of CD4- and CD8-positive T lymphocytes and Mac3-positive macrophages. Adiponectin provision by adenovirus in APN-/- mice reversed these exacerbated responses to allografting. The rejected allografts in APN-/- mice contained significantly higher levels of tumor necrosis factor-alpha, interferon-gamma, and regulated on activation normal t expressed and presumably secreted. Moreover, adiponectin significantly suppressed proliferation and production of tumor necrosis factor-alpha, interferon-gamma, regulated on activation normal t expressed and presumably secreted, monocyte chemotactic protein-1, and interferon-gamma inducible protein-10 in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.These observations provide new mechanistic insight into immunoregulation in allograft recipients relative to obesity, an increasingly prevalent risk factor. Adiponectin may offer a new therapeutic target for allograft rejection after cardiac transplantation.

Project description:BACKGROUND:The calcium-binding proteins myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) form MRP-8/14 heterodimers (S100A8/A9, calprotectin) that regulate myeloid cell function and inflammatory responses and serve as early serum markers for monitoring acute allograft rejection. Despite functioning as a proinflammatory mediator, the pathophysiological role of MRP-8/14 complexes in cardiovascular disease is incompletely defined. This study investigated the role of MRP-8/14 in cardiac allograft rejection using MRP-14(-/-) mice that lack MRP-8/14 complexes. METHODS AND RESULTS:We examined parenchymal rejection after major histocompatibility complex class II allomismatched cardiac transplantation (bm12 donor heart and B6 recipients) in wild-type (WT) and MRP-14(-/-) recipients. Allograft survival averaged 5.9±2.9 weeks (n=10) in MRP-14(-/-) recipients compared with >12 weeks (n=15; P<0.0001) in WT recipients. Two weeks after transplantation, allografts in MRP-14(-/-) recipients had significantly higher parenchymal rejection scores (2.8±0.8; n=8) than did WT recipients (0.8±0.8; n=12; P<0.0001). Compared with WT recipients, allografts in MRP-14(-/-) recipients had significantly increased T-cell and macrophage infiltration and increased mRNA levels of interferon-? and interferon-?-associated chemokines (CXCL9, CXCL10, and CXCL11), interleukin-6, and interleukin-17 with significantly higher levels of Th17 cells. MRP-14(-/-) recipients also had significantly more lymphocytes in the adjacent para-aortic lymph nodes than did WT recipients (cells per lymph node: 23.7±0.7×10(5) for MRP-14(-/-) versus 6.0±0.2×10(5) for WT; P<0.0001). The dendritic cells (DCs) of the MRP-14(-/-) recipients of bm12 hearts expressed significantly higher levels of the costimulatory molecules CD80 and CD86 than did those of WT recipients 2 weeks after transplantation. Mixed leukocyte reactions with allo-endothelial cell-primed MRP-14(-/-) DCs resulted in significantly higher antigen-presenting function than reactions using WT DCs. Ovalbumin-primed MRP-14(-/-) DCs augmented proliferation of OT-II (ovalbumin-specific T cell receptor transgenic) CD4(+) T cells with increased interleukin-2 and interferon-? production. Cardiac allografts of B6 major histocompatibility complex class II(-/-) hosts and of B6 WT hosts receiving MRP-14(-/-) DCs had significantly augmented inflammatory cell infiltration and accelerated allograft rejection compared with WT DCs from transferred recipient allografts. Bone marrow-derived MRP-14(-/-) DCs infected with MRP-8 and MRP-14 retroviral vectors showed significantly decreased CD80 and CD86 expression compared with controls, indicating that MRP-8/14 regulates B7-costimulatory molecule expression. CONCLUSIONS:Our results indicate that MRP-14 regulates B7 molecule expression and reduces antigen presentation by DCs and subsequent T-cell priming. The absence of MRP-14 markedly increased T-cell activation and exacerbated allograft rejection, indicating a previously unrecognized role for MRP-14 in immune cell biology.

Project description:AimAllograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologists.Methods and resultsThe study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The 'Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader' pipeline was trained using an interpretable, biologically inspired, 'hand-crafted' feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the 'grade of record', testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement [95% confidence interval (CI): 55.2-66.0%] with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0-65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4-68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3-64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P < 0.001).ConclusionThese results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.

Project description:BackgroundCardiac allograft rejection remains a significant clinical problem in the early phase after heart transplantation and requires frequent surveillance with endomyocardial biopsy. However, this is an invasive procedure, which is unpleasant for the patient and carries a certain risk. Therefore, a sensitive non-invasive biomarker of acute rejection would be desirable.MethodsEndomyocardial tissue samples and serum were obtained in connection with clinical biopsies from twenty consecutive heart transplant patients followed for six months. A rejection episode was observed in 14 patients (11 men and 3 women) and biopsies obtained before, during and after the episode were identified. Endomyocardial RNA, from three patients, matching these three points in time were analysed with DNA microarray. Genes showing up-regulation during rejection followed by normalization after the rejection episode were evaluated further with real-time RT-PCR. Finally, ELISA was performed to investigate whether change in gene-regulation during graft rejection was reflected in altered concentrations of the encoded protein in serum.ResultsThree potential cardiac allograft rejection biomarker genes, chemokine (C-X-C motif) ligand 9 (CXCL9), chemokine (C-X-C motif) ligand 10 (CXCL10) and Natriuretic peptide precursor A (NPPA), from the DNA microarray analysis were selected for further evaluation. CXCL9 was significantly upregulated during rejection (p < 0.05) and CXCL10 displayed a similar pattern without reaching statistical significance. Serum levels of CXCL9 and CXCL10 were measured by ELISA in samples from 10 patients before, during and after cardiac rejection. There were no changes in CXCL9 and CXCL10 serum concentrations during cardiac rejection. Both chemokines displayed large individual variations in the selected samples, but the serum levels between the two chemokines correlated (p < 0.001).ConclusionWe conclude, that despite a distinct up-regulation of CXCL9 mRNA in human hearts during cardiac allograft rejection, this was not reflected in the serum levels of the encoded protein. Thus, in contrast to previous suggestions, serum CXCL9 does not appear to be a promising serum biomarker for cardiac allograft rejection.

Dataset Information

A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice.

Publications

A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice.

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