MicroRNAs as theranostic markers in cardiac allograft transplantation: from murine models to clinical practice.
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ABSTRACT:
SUBMITTER: Novak J
PROVIDER: S-EPMC8058726 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
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Project description:Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4-Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.
| S-EPMC8410061 | biostudies-literature
Project description:Acute allograft rejection is a serious and life-threatening complication of organ transplantation. Th17 cells induced inflammation has been described to play an important role in allograft rejection. Since there is a plenty of evidence indicating that transcriptional factor BATF regulates the differentiation of Th17 and follicular T helper cells both in vitro and in vivo, we investigated whether is BATF involved in acute rejection and allograft survival by injecting lentivirus containing BATF shRNA through tail vein before the cardiac transplantation operation. We found that the allograft survival time of the mice treated with BATF shRNA was significantly prolonged compared with that of negative shRNA treated group and the control group. Further pathological analysis revealed that the BATF shRNA treatment group had significantly lower rejection degree than the negative shRNA group, while there was no significant difference between the negative shRNA group and the control group. Furthermore, flow cytometry analysis and quantitative polymerase chain reaction and enzyme-linked immuno sorbent assay were used to determine the proportion of T helper cells, the expression of specific transcription factor and the inflammatory cytokines respectively. Data showed that BATF regulated Th17 and Treg responses during allograft rejection. And BATF inhibition led to reduction of the expression level of Rorγ-t and enhancement of the Foxp-3. In addition, cytokines IL-17A and IL-4 were found decreased. This may indicate BATF as a novel therapy target for treatment of acute allograft rejection.
| S-EPMC5009413 | biostudies-literature
Project description:MicroRNAs are implicated in many biological and pathological processes and are emerging as key actors in lung health and disease. Specific patterns of dysregulated microRNAs have been found in idiopathic pulmonary fibrosis (IPF), an untreatable interstitial lung disease of unknown etiology. IPF is characterized by dramatic and extensive phenotypic changes in the lung that include alveolar cell hyperplasia, fibroblast proliferation and formation of myofibroblast foci, deposition of extracellular matrix, and changes in lung transcriptional programming. Here, we discuss the latest insights about the role of microRNAs in lung fibrosis with a focus on the contribution of animal models of disease to the derivation of these insights.
| S-EPMC4201640 | biostudies-literature
Project description:Surgical strategies for knee joint preservation are numerous, with the procedure(s) of choice for a given patient dependent on the status of the articular cartilage, meniscus, overall alignment, and ligamentous stability. For patients with large, isolated, osteochondral defects of the articular cartilage of the femoral condyle, osteochondral allograft transplantation (OCA) is often performed in an effort to reduce pain and improve function. Similarly, for appropriately indicated patients with symptomatic meniscus deficiency, meniscus allograft transplantation (MAT) is an excellent surgical solution. Often patients require concomitant MAT and OCA as part of a joint preservation strategy. In this Technical Note, we describe the surgical technique for performing arthroscopic-assisted concomitant lateral MAT and lateral femoral condyle OCA as part of a knee joint preservation strategy.
| S-EPMC5710720 | biostudies-literature
Project description:PurposeTo assess the clinical effectiveness and cost-effectiveness of meniscal allograft transplantation (MAT) after meniscal injury and subsequent meniscectomy.MethodsSystematic review of clinical effectiveness and cost-effectiveness analysis.ResultsThere is considerable evidence from observational studies, of improvement in symptoms after meniscal allograft transplantation, but we found only one small pilot trial with a randomised comparison with a control group that received non-surgical care. MAT has not yet been proven to be chondroprotective. Cost-effectiveness analysis is not possible due to a lack of data on the effectiveness of MAT compared to non-surgical care.ConclusionThe benefits of MAT include symptomatic relief and restoration of at least some previous activities, which will be reflected in utility values and hence in quality-adjusted life years, and in the longer term, prevention or delay of osteoarthritis, and avoidance or postponement of some knee replacements, with resulting savings. It is likely to be cost-effective, but this cannot be proven on the basis of present evidence.Level of evidenceIV.
| S-EPMC6541576 | biostudies-literature
Project description:ObjectiveMurine models have proved instrumental in studying various aspects of abdominal aortic aneurysm (AAA), from identification of underlying pathophysiologic changes to the development of novel therapeutic strategies. In the current study, we describe a new model in which an elastase-treated donor aorta is transplanted to a recipient mouse and allowed to progress to aneurysm. We hypothesized that by transplanting an elastase-treated abdominal aorta of one genotype to a recipient mouse of a different genotype, one can differentiate pathophysiologic factors that are intrinsic to the aortic wall from those stemming from circulation and other organs.MethodsElastase-treated aorta was transplanted to the infrarenal abdominal aorta of recipient mice by end-to-side microsurgical anastomosis. Heat-inactivated elastase-treated aorta was used as a control. Syngeneic transplants were performed with use of 12-week-old C57BL/6 littermates. Transplant grafts were harvested from recipient mice on day 7 or day 14 after surgery. The aneurysm outcome was measured by aortic expansion, elastin degradation, proinflammatory cytokine expression, and inflammatory cell infiltration and compared with that produced with the established, conventional elastase infusion model.ResultsThe surgical technique success rate was 75.6%, and the 14-day survival rate was 51.1%. By day 14 after surgery, all of the elastase-treated transplanted abdominal aortas had dilated and progressed to AAAs, defined as 100% or more increase in the maximal external diameter compared with that measured before elastase perfusion, whereas none of the transplanted aortas pretreated with inactive elastase became aneurysmal (percentage increase in maximum aortic diameter: 159.36% ± 23.27%, transplanted elastase, vs 41.46% ± 9.34%, transplanted inactive elastase). Aneurysm parameters, including elastin degradation and infiltration of macrophages and T lymphocytes, were found to be identical to those observed in the conventional elastase model. Quantitative polymerase chain reaction analysis revealed similarly increased levels of proinflammatory cytokines (relative changes of mRNA in the conventional elastase model vs transplant model: tumor necrosis factor α, 1.71 ± 0.27 vs 2.93 ± 0.86; monocyte chemoattractant protein 1, 2.36 ± 0.58 vs 2.87 ± 0.51; chemokine (C-C motif) ligand 5, 3.37 ± 0.92 vs 3.46 ± 0.83; and interferon γ, 3.09 ± 0.83 vs 5.30 ± 1.69). Using green fluorescent protein transgenic mice as donors or recipients, we demonstrated that a small quantity of mononuclear leukocytes in the transplant grafts bared the genotype of the donors.ConclusionsTransplanted elastase-treated abdominal aorta could develop to aneurysm in recipient mice. This AAA transplant model can be used to examine how the microenvironment of a transplanted aneurysmal aorta may be altered by the contributions of the "global" environment of the recipient.
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Project description:BackgroundIntrauterine hematopoietic stem cell transplantation (IUT), potentially curative in congenital haematological disease, is often inhibited by deleterious immune responses to donor cells resulting in subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into transplanted recipients across the placenta may directly influence donor-specific alloresponsiveness, limiting DCC. We hypothesized that dendritic cells (DC) among trafficked MMc influence the development of tolerogenic or immunogenic responses towards donor cells, and investigated if maternal DC-depletion reduced recipient alloresponsiveness and enhanced DCC.MethodsUsing transgenic CD11c.DTR (C57BL/6) female mice enabled transient maternal DC-depletion with a single dose of diphtheria toxin (DT). CD11c.DTR females and BALB/c males were cross-mated, producing hybrid pups. IUT was performed at E14 following maternal DT administration 24 h prior. Bone marrow-derived mononuclear cells were transplanted, obtained from semi-allogenic BALB/c (paternal-derived; pIUT), C57BL/6 (maternal-derived; mIUT), or fully allogenic (aIUT) C3H donor mice. Recipient F1 pups were analyzed for DCC, while maternal and IUT-recipient immune cell profile and reactivity were examined via mixed lymphocyte reactivity functional assays. T- and B-cell receptor repertoire diversity in maternal and recipient cells were examined following donor cell exposure.ResultsDCC was highest and MMc was lowest following pIUT. In contrast, aIUT recipients had the lowest DCC and the highest MMc. In groups that were not DC-depleted, maternal cells trafficked post-IUT displayed reduced TCR & BCR clonotype diversity, while clonotype diversity was restored when dams were DC-depleted. Additionally, recipients displayed increased expression of regulatory T-cells and immune-inhibitory proteins, with reduced proinflammatory cytokine and donor-specific antibody production. DC-depletion did not impact initial donor chimerism. Postnatal transplantation without immunosuppression of paternal donor cells did not increase DCC in pIUT recipients; however there were no donor-specific antibody production or immune cell changes.ConclusionsThough maternal DC depletion did not improve DCC, we show for the first time that MMc influences donor-specific alloresponsiveness, possibly by expanding alloreactive clonotypes, and depleting maternal DC promotes and maintains acquired tolerance to donor cells independent of DCC, presenting a novel approach to enhancing donor cell tolerance following IUT. This may have value when planning repeat HSC transplantations to treat haemoglobinopathies.
| S-EPMC10206581 | biostudies-literature
Project description:Although activation of hedgehog (Hh) signaling has been shown to induce osteogenic differentiation in vitro and bone formation in vivo, the underlying mechanisms and the potential use of Hh-activated mesenchymal progenitors in bone defect repair remain elusive. In this study, we demonstrated that implantation of periosteal-derived mesenchymal progenitor cells (PDMPCs) that overexpressed an N-terminal sonic hedgehog peptide (ShhN) via an adenoviral vector (Ad-ShhN) restored periosteal bone collar formation in a 4-mm segmental bone allograft model in immunodeficient mice. Ad-ShhN enhanced donor cell survival and microvessel formation in collagen scaffold at 2 weeks after surgery and induced donor cell-dependent bone formation at 6 weeks after surgery. Fluorescence-activated cell sorting analysis further showed that Ad-ShhN-PDMPC-seeded scaffold contained a twofold more CD45(-)Sca-1(+)CD34(+)VEGFR2(+) endothelial progenitors than Ad-LacZ-PDMPC-seeded scaffold at day 7 after surgery. Ad-ShhN-transduced PDMPCs induced a 1.8-fold more CD31(+) microvessel formation than Ad-LacZ-transduced PDMPCs in a coculture of endothelial progenitors and PDMPCs. Taken together, our data show that overexpression of ShhN in mesenchymal progenitors improves bone defect reconstruction by enhancing donor progenitor cell survival, differentiation, and scaffold revascularization at the site of compromised periosteum. Hh agonist-based therapy, therefore, merits further investigation in tissue engineering-based applications aimed at enhancing bone defect repair and reconstruction.
| S-EPMC3916037 | biostudies-literature
Project description:Meniscal tears treated with partial meniscectomies have been shown to significantly increase contract pressures within the tibiofemoral joint, and a complete focal meniscal deficiency may render the entirety of the meniscus functionally incompetent. Although various techniques of meniscal transplantation have been described, these techniques may require the excision of a considerable amount of healthy meniscal tissue. Furthermore, failures continue to frequently occur. Therefore, attempts to restoring normal knee kinematics and biomechanical forces are essential. Segmental meniscus allograft transplantations may offer the advantage of a robust repair by both maintaining knee biomechanics and biology while maximizing preservation of native meniscal tissue. Also, most meniscal deficiency involves only a portion of the meniscus, and thus we developed this technique to segmentally transplant only the deficient portion. The purpose of this Technical Note is to describe a technique of segmental medial meniscus allograft transplantation in a patient with focal medial meniscus deficiency.
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