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1.
Haematologica ; 106(8): 2147-2160, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32675225

RESUMO

Clinical studies suggested that endothelial dysfunction and damage could be involved in the development and severity of acute graft-versus-host disease (aGVHD). Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGVHD. In murine experimental aGVHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGVHD target organs. During intestinal aGVHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. Because recent data demonstrated an association of endothelium-related factors and steroid refractory aGVHD (SR-aGVHD), we analyzed human biopsies and murine tissues from SR-aGVHD. We found extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent SR-aGVHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGVHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGVHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGVHD complementing current anti-inflammatory treatment options.


Assuntos
Doença Enxerto-Hospedeiro , Animais , Células Endoteliais , Endotélio , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Camundongos , Esteroides , Linfócitos T
2.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201218

RESUMO

Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic "window of opportunity" is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool.


Assuntos
Antineoplásicos/toxicidade , Blefarite/patologia , Córnea/irrigação sanguínea , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Inflamação/patologia , Aparelho Lacrimal/patologia , Animais , Blefarite/etiologia , Blefarite/metabolismo , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Aparelho Lacrimal/metabolismo , Linfangiogênese , Camundongos , Camundongos Endogâmicos C57BL
3.
Int J Mol Sci ; 22(1)2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33383915

RESUMO

The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology.


Assuntos
Células da Medula Óssea/metabolismo , Remodelação Óssea , Animais , Biomarcadores , Medula Óssea/metabolismo , Medula Óssea/patologia , Diáfises , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Imunofenotipagem , Camundongos , Osteoblastos/imunologia , Osteoblastos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Quimeras de Transplante , Transplante Homólogo
4.
Blood ; 129(13): 1865-1875, 2017 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-28096093

RESUMO

Lymph vessels play a crucial role in immune reactions in health and disease. In oncology the inhibition of lymphangiogenesis is an established therapeutic concept for reducing metastatic spreading of tumor cells. During allogeneic tissue transplantation, the inhibition of lymphangiogenesis has been successfully used to attenuate graft rejection. Despite its critical importance for tumor growth, alloimmune responses, and inflammation, the role of lymphangiogenesis has not been investigated during allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that acute graft-versus-host disease (aGVHD) is associated with lymphangiogenesis in murine allo-HSCT models as well as in patient intestinal biopsies. Inhibition of aGVHD-associated lymphangiogenesis by monoclonal antibodies against vascular endothelial growth factor receptor 3 (VEGFR-3) ameliorated aGVHD and improved survival in murine models. The administration of anti-VEGFR-3 antibodies did not interfere with hematopoietic engraftment and improved immune reconstitution in allo-HSCT recipients with aGVHD. Anti-VEGFR-3 therapy had no significant impact on growth of malignant lymphoma after allo-HSCT. We conclude that aGVHD is associated with lymphangiogenesis in intestinal lesions and in lymph nodes. Our data show that anti-VEGFR-3 treatment ameliorates lethal aGVHD and identifies the lymphatic vasculature as a novel therapeutic target in the setting of allo-HSCT.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Linfangiogênese , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Enteropatias , Linfonodos/patologia , Camundongos , Transplante Homólogo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/imunologia
5.
Blood ; 129(14): 2021-2032, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28096092

RESUMO

The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue-infiltrating leukocytes. However, it is not known if angiogenesis has an active role during the initiation of inflammation or if it is merely a secondary effect occurring in response to stimuli by tissue-infiltrating leukocytes. Here, we show that angiogenesis precedes leukocyte infiltration in experimental models of inflammatory bowel disease and acute graft-versus-host disease (GVHD). We found that angiogenesis occurred as early as day+2 after allogeneic transplantation mainly in GVHD typical target organs skin, liver, and intestines, whereas no angiogenic changes appeared due to conditioning or syngeneic transplantation. The initiation phase of angiogenesis was not associated with classical endothelial cell (EC) activation signs, such as Vegfa/VEGFR1+2 upregulation or increased adhesion molecule expression. During early GVHD at day+2, we found significant metabolic and cytoskeleton changes in target organ ECs in gene array and proteomic analyses. These modifications have significant functional consequences as indicated by profoundly higher deformation in real-time deformability cytometry. Our results demonstrate that metabolic changes trigger alterations in cell mechanics, leading to enhanced migratory and proliferative potential of ECs during the initiation of inflammation. Our study adds evidence to the hypothesis that angiogenesis is involved in the initiation of tissue inflammation during GVHD.


Assuntos
Doença Enxerto-Hospedeiro/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Doença Aguda , Aloenxertos , Animais , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
6.
Blood ; 121(17): 3307-18, 2013 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-23327924

RESUMO

Acute graft-versus-host disease (GvHD) is a complex process involving endothelial damage and neovascularization. Better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T-cell function intact. Under ischemic conditions, neovascularization is regulated by different micro RNAs (miRs), which potentially play a role in inflamed hypoxic GvHD target organs. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron emission tomography imaging demonstrated abundant αvß3 integrin expression within intestinal neovascularization areas. To interfere with neovascularization, we targeted αv integrin-expressing endothelial cells, which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αv integrin expression correlated with GvHD severity in humans. Expression analysis of miRs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αv integrin. We identify negative regulation of GvHD-related neovascularization by miR-100, which indicates common pathomechanistic features of GvHD and ischemia.


Assuntos
Doença Enxerto-Hospedeiro/complicações , Inflamação/etiologia , Integrina alfaV/metabolismo , Enteropatias/etiologia , MicroRNAs/genética , Neovascularização Patológica , Animais , Western Blotting , Transplante de Medula Óssea , Feminino , Citometria de Fluxo , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Humanos , Técnicas Imunoenzimáticas , Inflamação/metabolismo , Inflamação/patologia , Integrina alfaV/genética , Enteropatias/metabolismo , Enteropatias/patologia , Medições Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Tomografia por Emissão de Pósitrons , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
Leukemia ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38918561

RESUMO

There is no consensus on second allogeneic stem cell transplantation (alloSCT) indications in patients with hematologic malignancies relapsing after a first alloSCT. In historic publications, a very high non-relapse mortality (NRM) has been described, arguing against performing a second alloSCT. We analysed the outcome of 3356 second alloSCTs performed 2011-21 following a hematologic malignancy relapse. Outcomes at two years after second alloSCT were: NRM 22%, relapse incidence 50%, overall survival 38%, and progression-free survival 28%. Key risk factors for increased NRM were: older age, low performance score, high disease-risk-index, early relapse after the first alloSCT, unrelated/haploidentical donor, and GVHD before second alloSCT. Any type of GVHD after first alloSCT was also important risk factor for acute GVHD and chronic GVHD after second alloSCT. There was a preferential use of a different donor (80%) at second alloSCT from first alloSCT. However, in multivariate analysis, the use of the same alloSCT donor for second alloSCT vs. a different donor was not associated with any of the survival or GVHD endpoints. We show considerably improved outcome as compared to historic reports. These current data support a wider use of second alloSCT and provide risk factors for NRM that need to be considered.

8.
Histopathology ; 63(2): 157-66, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23808822

RESUMO

AIMS: Pancreatic ductal adenocarcinomas (PDACs) are chemoresistant, resulting in extremely poor survival of patients; therefore, novel molecular targets, even in small subsets of genetically characterized tumours, are urgently needed. Tyrosine kinase receptor inhibitors (TKIs) are already in clinical use. The aims of this study were to examine the gene copy number and expression of fibroblast growth factor receptor 1 (FGFR1) in 155 patients with PDAC, and investigate the effects of the FGFR-specific inhibitor BGJ398 on FGFR1-amplified pancreatic tumour cells in vitro. METHODS AND RESULTS: Fluorescence in-situ hybridization (FISH) and immunohistochemical analysis of 155 PDACs were performed using tissue microarrays. Amplification of FGFR1 was found in 2.6% (4/155) of cases. Four per cent of tumours (5/125) were shown to express FGFR1 by immunohistochemistry. Sequence analysis demonstrated an activating KRAS mutation (exon 2) in all FGFR1-amplified cases. The FGFR1-amplified pancreatic carcinoma cell line PT45P1 showed high levels of FGFR1 mRNA and protein expression. Proliferation of this cell line can be inhibited using the FGFR1 inhibitor BGJ398. CONCLUSIONS: FGFR1 represents a potential new therapeutic target in a subset of patients harbouring FGFR1-amplified tumours. Identification of pancreatic cancers harbouring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using TKIs.


Assuntos
Carcinoma Ductal Pancreático/genética , Amplificação de Genes , Neoplasias Pancreáticas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Análise Serial de Tecidos , Proteínas ras/genética
9.
BMC Cancer ; 12: 85, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-22401174

RESUMO

BACKGROUND: Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (DR4) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed DR4 mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC. METHODS: Frequencies of DR4 gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population. RESULTS: Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. DR4 variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10(6) IU/ml vs. 1.81 ± 0.23 × 10(6) IU/ml, p = 0.049). CONCLUSIONS: The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.


Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Hepatite C/complicações , Neoplasias Hepáticas/genética , Polimorfismo Genético , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Carcinoma Hepatocelular/virologia , Feminino , Frequência do Gene , Genótipo , Humanos , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Modelos de Riscos Proporcionais
10.
Front Immunol ; 13: 1079921, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36761159

RESUMO

Despite considerable progress in allogeneic hematopoietic cell transplantation (allo-HCT) has been achieved over the past years, chronic Graft-versus-Host Disease (cGvHD) still contributes to high morbidity rates, thus remaining a major hurdle in allo-HCT patients. To understand the complex pathophysiology of cGvHD and to develop refined prophylaxis and treatment strategies, improved pre-clinical models are needed. In this study, we developed two murine cGvHD models, which display high long-term morbidity but low mortality and depict the heterogeneous clinical manifestations of cGvHD seen in patients. We established a haploidentical C57BL/6→B6D2F1 allo-HCT model that uses myeloablative radiation and G-CSF-mobilized splenocytes as stem cell source and a sub-lethally irradiated Xenograft model, which utilizes the transfer of human peripheral blood mononuclear cells (PBMCs) into NOD scid gamma (NSG)-recipients. We characterized both mouse models to exhibit diverse clinical and histopathological signs of human cGvHD as extensive tissue damage, fibrosis/sclerosis, inflammation and B cell infiltration in cGvHD target organs skin, liver, lung and colon and found a decelerated immune cell reconstitution in the late phase after HCT. Our pre-clinical models can help to gain a deeper understanding of the target structures and mechanisms of cGvHD pathology and may enable a more reliable translation of experimental findings into the human setting of allo-HCT.


Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Humanos , Camundongos , Animais , Leucócitos Mononucleares/patologia , Transplante Homólogo/efeitos adversos , Camundongos Endogâmicos C57BL
12.
Front Immunol ; 11: 1983, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849661

RESUMO

Despite its involvement in various immune functions, including the allogeneic activation of T-lymphocytes, the relevance of calcium (Ca2+) for GVHD pathobiology is largely unknown. To elucidate a potential association between Ca2+and GVHD, we analyzed Ca2+-sensing G-protein coupled receptor 6a (GPRC6a) signaling in preclinical GVHD models and conducted a prospective EBMT study on Ca2+ serum levels prior alloSCT including 363 matched sibling allogeneic peripheral blood stem cell transplantations (alloSCTs). In experimental models, we found decreased Gprc6a expression during intestinal GVHD. GPRC6a deficient alloSCT recipients had higher clinical and histopathological GVHD scores leading to increased mortality. As possible underlying mechanism, we found increased antigen presentation potential in GPRC6a-/- alloSCT recipients demonstrated by higher proliferation rates of T-lymphocytes. In patients with low Ca2+ serum levels (≤median 2.2 mmol/l) before alloSCT, we found a higher incidence of acute GVHD grades II-IV (HR = 2.3 Cl = 1.45-3.85 p = 0.0006), severe acute GVHD grades III-IV (HR = 3.3 CI = 1.59-7.14, p = 0.002) and extensive chronic GVHD (HR = 2.0 Cl = 1.04-3.85 p = 0.04). In conclusion, experimental and clinical data suggest an association of reduced Ca2+ signaling with increased severity of GVHD. Future areas of interest include the in depth analysis of involved molecular pathways and the investigation of Ca2+ signaling as a therapeutic target during GVHD.


Assuntos
Sinalização do Cálcio , Suscetibilidade a Doenças , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Animais , Biomarcadores , Cálcio/sangue , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunofenotipagem , Incidência , Leucócitos/imunologia , Leucócitos/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Prognóstico , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Recidiva , Transplante Homólogo
13.
Front Immunol ; 10: 2339, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31649666

RESUMO

Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed in vitro studies using endothelial cell (EC) lines. We found that DF significantly and dose-dependently suppressed EC proliferation and notably reduced their ability to form vascular tubes in Matrigel. To explore whether DF administered prophylactically or therapeutically has a significant effect on aGVHD endothelial dysfunction, ECs were exposed to media containing sera from patients with aGVHD (n = 22) in the absence or presence of DF and from patients that did not develop aGVHD (n = 13). ECs upregulated adhesion molecules (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), the adherence junction protein VE-cadherin, von Willebrand factor (VWF), and Akt phosphorylation in response to aGVHD sera. These responses were suppressed upon treatment with DF. In summary, DF inhibits vascular angiogenesis and endothelial activation induced by sera from aGVHD patients. Our results support the view that DF has notable positive effects on endothelial biology during aGVHD.


Assuntos
Endotélio/metabolismo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Polidesoxirribonucleotídeos/administração & dosagem , Doença Aguda , Endotélio/patologia , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Masculino
14.
Front Immunol ; 8: 203, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28298913

RESUMO

Microbial products influence immunity after allogeneic hematopoietic stem cell transplantation (allo-SCT). In this context, the role of cathepsin E (Ctse), an aspartate protease known to cleave bacterial peptides for antigen presentation in dendritic cells (DCs), has not been studied. During experimental acute graft-versus-host disease (GVHD), we found infiltration by Ctse-positive immune cells leading to higher Ctse RNA- and protein levels in target organs. In Ctse-deficient allo-SCT recipients, we found ameliorated GVHD, improved survival, and lower numbers of tissue-infiltrating DCs. Donor T cell proliferation was not different in Ctse-deficient vs. wild-type allo-SCT recipients in MHC-matched and MHC-mismatched models. Furthermore, Ctse-deficient DCs had an intact ability to induce allogeneic T cell proliferation, suggesting that its role in antigen presentation may not be the main mechanism how Ctse impacts GVHD. We found that Ctse deficiency significantly decreases DC motility in vivo, reduces adhesion to extracellular matrix (ECM), and diminishes invasion through ECM. We conclude that Ctse has a previously unrecognized role in regulating DC motility that possibly contributes to reduced DC counts and ameliorated inflammation in GVHD target organs of Ctse-deficient allo-SCT recipients. However, our data do not provide definite proof that the observed effect of Ctse-/- deficiency is exclusively mediated by DCs. A contribution of Ctse-/--mediated functions in other recipient cell types, e.g., macrophages, cannot be excluded.

15.
Antivir Ther ; 16(7): 1047-55, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22024520

RESUMO

BACKGROUND: Recently, we identified increased rates of CD4(+) T-cell apoptosis in HCV-infected HIV-positive patients as a potential mechanism for enhanced mortality in patients with HIV/HCV coinfection. Since this effect might be attributed to changes in receptor-induced apoptosis, we studied expression and function of Fas ligand (FasL) and its death receptor Fas on CD4(+) T-cells in HIV/HCV coinfection. METHODS: In this cross-sectional study, we simultaneously analysed surface expression of Fas and FasL on CD4(+) T-cells and serum levels of soluble FasL in HCV/HIV-coinfected, HIV-monoinfected and HCV-monoinfected patients. Susceptibility to FasL-induced apoptosis was analysed by incubating isolated peripheral blood mononuclear cells with rhFasL followed by measuring CD4(+) T-cell apoptosis. RESULTS: HIV and HCV monoinfection were associated with significantly enhanced surface expression of Fas. Highest Fas expression was detected in HIV/HCV-coinfected patients and correlated with low CD4(+) T-cell counts. By contrast, elevated levels of soluble and cellular FasL were found only in patients with HIV infection, but not in patients with HCV infection. Importantly, enhanced Fas expression in HCV/HIV coinfection rendered CD4(+) T-cells more susceptible towards FasL-induced apoptosis. While effective HAART normalized expression and secretion of FasL in HIV-infected and HIV/HCV-coinfected patients, expression of Fas decreased only slightly and still remained significantly elevated as compared with healthy controls. CONCLUSIONS: Our findings suggest a synergistic mechanism in HIV/HCV coinfection between up-regulation of Fas expression on CD4(+) T-cells and HIV-induced elevated levels of cellular and soluble FasL. Together, both effects contribute to enhanced apoptosis of CD4(+) T-cells in HIV/HCV coinfection.


Assuntos
Apoptose , Linfócitos T CD4-Positivos/fisiologia , Proteína Ligante Fas/metabolismo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepatite C/complicações , Receptor fas/metabolismo , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Coinfecção , Feminino , Infecções por HIV/imunologia , HIV-1/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptor fas/sangue
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