C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 play key roles in the initiation and development of acute transplant rejection. Previously, higher levels of RANTES expression and secretion were demonstrated in retransplantation or T-cell memory-transfer models. In the present study, the effect of the chemokines, CXCL9 and CXCL10, were investigated in a mouse retransplantation model. BALB/c mice were used as donors, while C57BL/6 mice were used as recipients. In the experimental groups, a heterotopic heart transplantation was performed six weeks following skin grafting. In the control groups, a heterotopic heart transplantation was performed without skin grafting. Untreated mice served as blank controls. The mean graft survival time of the heterotopic heart transplantations was 7.7 days in the experimental group (n=6), as compared with 3.25 days in the control group (n=6; P<0.001). On day three following cardiac transplantation, histological evaluation of the grafts revealed a higher International Society for Heart & Lung Transplantation grade in the experimental group as compared with the control group. In addition, gene expression and serum concentrations of CXCL9, CXCL10, interferon-γ, and interleukin-2 were markedly higher in the experimental group when compared with the control group. Differences between the levels of CXCL9 and CXCL10 in the pre- and post-transplant mice indicated that the chemokines may serve as possible biomarkers to predict acute rejection. The results of the present study demonstrated that CXCL9 and CXCL10 play a critical role in transplantation and retransplantation. High levels of these cytokines during the pre-transplant period may lead to extensive acute rejection. Thus, the observations enhance the understanding of the mechanism underlying the increased expression and secretion of CXCL9 and CXCL10 by alloreactive memory T cells.
epithelial-to-mesenchymal transition (eMT) in nasal epithelial cells is involved with tissue remodeling of nasal polyps. The present study investigated the molecular mechanisms through which mir-155-5p regulated eMT in chronic rhinosinusitis (crS). Patients were divided into the following groups: crSsnP, crS without nasal polyposis group, crSwnP, crS with nasal polyposis and controls. The expression of transforming growth factor (TGF)-β1, eMT markers, sirtuin 1 (SirT1) and mir-155-5p were determined by western blotting and reverse transcription-quantitative Pcr. cell morphology following TGF-β1 treatment in the presence of mir-155-5p inhibitors or controls was observed under a microscope. Target genes and potential binding sites between mir-155-5p and SirT1 were predicted by TargetScan and confirmed using dual-luciferase reporter assay. In patients with crS, the expression levels of e-cadherin were downregulated and the expression levels of TGF-β1, mesenchymal markers and mir-155-5p were upregulated. additionally, these changes in expression levels were reduced or increased to a greater extent in the crSwnP group compared with the crSsnP group. Furthermore, TGF-β1 expression promoted eMT in human nasal epithelial cells (Hnepcs) and upregulated mir-155-5p expression. These effects were reversed by mir-155-5p inhibitors. additionally, SirT1 was predicted as a target gene of mir-155-5p. downregulation of mir-155-5p upregulated epithelial marker expression and downregulated mesenchymal marker expression by regulating SirT1. Therefore, the downregulation of mir-155-5p inhibited eMT in Hnepcs by targeting SirT1.
The upregulation of chemokine genes and the subsequent T-lymphocyte recruitment to the graft are early events in the development of acute cardiac transplant rejection or cardiac allograft vasculopathy. In the present study, a combined immunosuppressive regimen of C-X-C motif chemokine 9 (CXCL9) antibody (Ab), CXCL10 Ab and FTY720 was used in order to reduce the infiltration of memory T lymphocytes and prolong graft survival in a retransplantation murine model. BALB/c donor hearts were transplanted heterotopically into C57BL/6 mice at day 28 after skin transplantation. The mice were divided into four groups: i) Control (normal saline), ii) CXCL9 Ab and CXCL10 Ab [150 μg; once daily (qd); intraperitoneal (ip)], iii) FTY720 (0.2 mg/day; qd; ip) and iv) combined (2 mg/kg/day; qd; ip). Measurements of the median survival time of the cardiac grafts, histological examination, reverse transcription-quantitative polymerase chain reaction analysis, enzyme-linked immunosorbent assay and a mixed lymphocyte reaction were performed. The median graft survival time of the combined group was prolonged (9.3 days) compared with that of the control group (3.5 days) (P<0.001). Histological examination revealed that the combined treatment group graft rejection pathological score was 0.50, while the control group score was 3.62 (P<0.001). In addition, the gene expression level of interleukin (IL)-2 was significantly lower and the levels of IL-10 and transforming growth factor-β (TGF-β) were significantly higher in the combined group compared with those in the control group (P<0.001). Furthermore, the serum concentration levels of IL-2 and interferon-γ (IFN-γ) were significantly lower (P<0.001) and the concentration of IL-10 was significantly higher (P<0.05) in the combined group compared with those in the control group. In the mixed lymphocyte reaction, T-cell proliferation was found to be significantly lower in the combined treatment group than that in the control group (P<0.001). In conclusion, treatment with CXCL9 Ab and CXCL10 Ab or FTY720 reduced the graft infiltration of inflammatory cells, inhibited T-cell proliferation and prolonged graft survival. The combined treatment regimen of CXCL9 Ab, CXCL10 Ab and FTY720 was found to significantly reduce the infiltration of inflammatory cells in the graft and prolong graft survival.
Abstract. The interaction of chemokine (C-X-C motif) ligand 10 (CXCL10) with its receptor (CXCR3) is a critical process in recruiting donor reactive T cells to a graft and alloantigen-specific memory T (Tm) cells exert a principal function in promoting graft dysfunction during accelerated cardiac rejection. However, whether CXCL10 chemokine exerts any effects on acute accelerated rejection mediated by CD8 + Tm cells in a re-transplant model has remained elusive. The present study established a cardiac transplant model by advanced microsurgery technology and improved organ storage. A novel rat model of cardiac re-transplantation was established at 40 days following primary heart transplant. The experiment included two parts, and when models were established, the rats were divided into two groups: Primary cardiac transplant (HTx) and re-transplantation without treatment (HRTx). In part 1, recipients from part 2, including re-transplantation without treatment (HRTx+NS) and re-transplantation treated with anti-CXCL10 antibodies (500 µg every other day by intraperitoneal injection; HRTx+CXCL10 Abs group). The graft survival time was observed and graft infiltration by inflammatory cells was assessed via histology of cardiac graft sections; in addition, the gene expression and the serum concentration of CXCL10 in each group was assessed. Indexes such as rejection-associated cytokines were assayed by reverse-transcription quantitative PCR and ELISA kits, and flow cytometry of splenocytes was used to detect Tm cells in the re-transplantation groups. The results demonstrated that level of CXCL10 was significantly increased and the graft mean survival time was shortened accompanied with aggravated lymphocyte cell infiltration in the HRTx group when compared that in the HTx group; in addition, the serum levels and mRNA expression of interleukin (IL)-2 and interferon (IFN)-γ were increased, while transforming growth factor (TGF)-β was decreased in the HRTx group. Furthermore, neutralization of CXCL10 prolonged the graft mean survival time and delayed accelerated rejection. Compared with that in the HRTx+NS group, serum levels and graft tissue mRNA expression of IFN-γ and IL-2 were decreased in the HRTx+CXCL10 Abs group, while TGF-β mRNA was significantly increased but the serum concentration was not significantly affected. In addition, there was no difference in IL-10 between the two groups, while delayed accelerated rejection paralleled with inflammatory cell infiltration decreased and the proliferation and differentiation of CD8 + Tm cells in secondary lymphoid organs were reduced in the HRTx+CXCL10 Abs group vs. those in the HRTx+NS group. The present study demonstrated that CXCL10 had a crucial role in cardiac transplantation and re-transplantation, and that treatment with CXCL10 antibodies delays accelerated acute rejection mediated by Tm cells in a rat model of cardiac re-transplantation. IntroductionA multidisciplinary program has been initiated to better establish transplantation for prolonging survival time of cardi...
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