Dataset Information

Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation.

ABSTRACT: Cellular protection against undesired effects of complement activation is provided by expression of membrane-bound complement regulatory proteins including CD59. This protein prevents membrane attack complex formation and is considered to be involved in graft accommodation. Also, CD59 downregulates CD4+ and CD8+ T-cell activation and proliferation. It is unknown whether CD59 expression is affected by transplantation. The aim of this study was to evaluate the quantitative CD59 antigen expression on distinct leukocyte subsets following lung transplantation (n?=?26) and to investigate whether this differs from pretransplantation (n?=?9). The results show that CD59 expression on leukocytes is significantly lower posttransplantation compared with healthy controls (p?=?0.002) and pretransplantation (p?

SUBMITTER: Michielsen LA

PROVIDER: S-EPMC5786830 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation.

Michielsen Laura A LA Budding Kevin K Drop Daniël D van de Graaf Ed A EA Kardol-Hoefnagel Tineke T Verhaar Marianne C MC van Zuilen Arjan D AD Otten Henny G HG

Frontiers in immunology 20180122

Cellular protection against undesired effects of complement activation is provided by expression of membrane-bound complement regulatory proteins including CD59. This protein prevents membrane attack complex formation and is considered to be involved in graft accommodation. Also, CD59 downregulates CD4+ and CD8+ T-cell activation and proliferation. It is unknown whether CD59 expression is affected by transplantation. The aim of this study was to evaluate the quantitative CD59 antigen expression ...[more]

PMID: 29403484

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Project description:The present study was conducted to generate transgenic pigs coexpressing human CD55, CD59, and H-transferase (HT) using an IRES-mediated polycistronic vector. The study focused on hyperacute rejection (HAR) when considering clinical xenotransplantation as an alternative source for human organ transplants. In total, 35 transgenic cloned piglets were produced by somatic cell nuclear transfer (SCNT) and were confirmed for genomic integration of the transgenes from umbilical cord samples by PCR analysis. Eighteen swine umbilical vein endothelial cells (SUVEC) were isolated from umbilical cord veins freshly obtained from the piglets. We observed a higher expression of transgenes in the transgenic SUVEC (Tg SUVEC) compared with the human umbilical vein endothelial cells (HUVEC). Among these genes, HT and hCD59 were expressed at a higher level in the tested Tg organs compared with non-Tg control organs, but there was no difference in hCD55 expression between them. The transgenes in various organs of the Tg clones revealed organ-specific and spatial expression patterns. Using from 0 to 50% human serum solutions, we performed human complement-mediated cytolysis assays. The results showed that, overall, the Tg SUVEC tested had greater survival rates than did the non-Tg SUVEC, and the Tg SUVEC with higher HT expression levels tended to have more down-regulated ?-Gal epitope expression, resulting in greater protection against cytotoxicity. By contrast, several Tg SUVEC with low CD55 expression exhibited a decreased resistance response to cytolysis. These results indicated that the levels of HT expression were inversely correlated with the levels of ?-Gal epitope expression and that the combined expression of hCD55, hCD59, and HT proteins in SUVECs markedly enhances a protective response to human serum-mediated cytolysis. Taken together, these results suggest that combining a polycistronic vector system with SCNT methods provides a fast and efficient alternative for the generation of transgenic large animals with multiple genetic modifications.

Project description:Several enveloped viruses including human immunodeficiency virus type 1 (HIV-1), cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), Ebola virus, vaccinia virus, and influenza virus have been found to incorporate host regulators of complement activation (RCA) into their viral envelopes and, as a result, escape antibody-dependent complement-mediated lysis (ADCML). Hepatitis C virus (HCV) is an enveloped virus of the family Flaviviridae and incorporates more than 10 host lipoproteins. Patients chronically infected with HCV develop high-titer and crossreactive neutralizing antibodies (nAbs), yet fail to clear the virus, raising the possibility that HCV may also use the similar strategy of RCA incorporation to escape ADCML. The current study was therefore undertaken to determine whether HCV virions incorporate biologically functional CD59, a key member of RCA. Our experiments provided several lines of evidence demonstrating that CD59 was associated with the external membrane of HCV particles derived from either Huh7.5.1 cells or plasma samples from HCV-infected patients. First, HCV particles were captured by CD59-specific Abs. Second, CD59 was detected in purified HCV particles by immunoblot analysis and in the cell-free supernatant from HCV-infected Huh7.5.1 cells, but not from uninfected or adenovirus serotype 5 (Ad5) (a nonenveloped cytolytic virus)-infected Huh7.5.1 cells by enzyme-linked immunosorbent assay. Last, abrogation of CD59 function with its blockers increased the sensitivity of HCV virions to ADCML, resulting in a significant reduction of HCV infectivity. Additionally, direct addition of CD59 blockers into plasma samples from HCV-infected patients increased autologous virolysis.Our study, for the first time, demonstrates that CD59 is incorporated into both cell line-derived and plasma primary HCV virions at levels that protect against ADCML. This is also the first report to show that direct addition of RCA blockers into plasma from HCV-infected patients renders endogenous plasma virions sensitive to ADCML.

Project description:BackgroundNeurobehavioral functioning is widely recognized as being an important consideration in lung transplant candidates, but little is known about whether these factors are related to clinical outcomes. The present study examined the relationship of neurobehavioral functioning, including measures of executive function and memory, depression, and anxiety, to long-term survival among lung transplant recipients.MethodsThe sample was drawn from 201 patients who underwent transplantation at Duke University and Washington University who participated in a dual-site clinical trial investigating medical and psychosocial outcomes in transplant candidates with end-stage lung disease. All patients completed the Beck Depression Inventory-II (BDI-II) and Spielberger State-Trait Anxiety Inventory at baseline and again after 12 weeks, while a subset of 86 patients from Duke University also completed neurocognitive testing. Patients were followed for survival up to 12 years after completing baseline assessments.ResultsOne hundred eleven patients died over a mean follow-up of 10.8 years (SD=0.8). Baseline depression, anxiety, and neurocognitive function were examined as predictors of posttransplant survival, controlling for age, 6-min walk distance, FEV, and native disease; education and cardiovascular risk factors were also included in the model for neurocognition. Lower executive function (hazard ratio [HR]=1.09, P=.012) and memory performance (HR=1.11, P=.030) were independently associated with greater mortality following lung transplant. Although pretransplant depression and anxiety were not predictive of mortality, patients who scored>13 on the BDI-II at baseline and after 3 months pretransplant had greater mortality (HR=1.85 [95% CI, 1.04, 3.28], P=.036).ConclusionsNeurobehavioral functioning, including persistently elevated depressive symptoms and lower neurocognitive performance, was associated with reduced survival after lung transplantation.Trial registryClinicalTrials.gov; No.: NCT00113139; URL: www.clinicaltrials.gov.

Dataset Information

Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation.

Publications

Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation.

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