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Biomedical subjects

C V Paya

Publications and source records attributed to C V Paya.

At least 109 records · Page 6Linked to original sources
PubMed1992

NF-kappa B-dependent induction of the NF-kappa B p50 subunit gene promoter underlies self-perpetuation of human immunodeficiency virus transcription in monocytic cells.

The molecular mechanisms underlying the sustained nuclear translocation of NF-kappa B observed in U937 monocytic cells chronically infected with human immunodeficiency virus (HIV) were studied. The activity of the promoter regulating the synthesis of the p105 precursor of the NF-kappa B p50 subunit was enhanced in these cells. Deletions in this promoter indicated that this upregulation was mediated through the NF-kappa B- but not the AP-1-binding motif, by bona fide p50/p65 heterodimers. Analysis of cytosolic extracts indicated that NF-kappa B levels were increased in HIV-infected cells. In contrast to the transient NF-kappa B activation induced by phorbol ester, the permanent NF-kappa B translocation induced by HIV infection was not dependent on PKC isoenzymes alpha and beta as shown by the use of a specific inhibitor (GF 109203X). These observations indicate that during chronic HIV infection of U937 cells, continuous NF-kappa B (p50/p65) translocation results in p105 promoter upregulation with subsequent cytosolic NF-kappa B accumulation, ready for further translocation. This HIV-mediated mechanism results in a self-perpetuating loop of NF-kappa B production.

Base Sequence↗
PubMed1992

Lack of association between cytomegalovirus infection, HLA matching and the vanishing bile duct syndrome after liver transplantation.

In this study we evaluated the association between cytomegalovirus infection alone or in relation to human leukocyte antigen matching and the development of vanishing bile duct syndrome, a form of chronic hepatic allograft rejection. A total of 81 consecutive liver transplant recipients were studied. Cytomegalovirus infection developed in 46 recipients (57%), and vanishing bile duct syndrome occurred in 9 recipients (11%). Cytomegalovirus infection developed in only five of the nine patients with vanishing bile duct syndrome. Univariate analysis of pretransplant recipient/donor cytomegalovirus serological tests and human leukocyte antigen typing showed they were not significant risk factors for the development of vanishing bile duct syndrome. Time-dependent analysis of cytomegalovirus infection after transplantation as a risk factor for vanishing bile duct syndrome, in a multivariate analysis with human leukocyte antigen match, showed no statistical significance. In our study, no association was found between cytomegalovirus infection alone or in relation to class I or II human leukocyte antigen match and the subsequent development of vanishing bile duct syndrome.

Acyclovir↗
PubMed1992

The characterization of the promoter of the gene encoding the p50 subunit of NF-kappa B indicates that it participates in its own regulation.

In order to characterize the regulation of the gene encoding the p50 subunit of the transcription factor NF-kappa B, we have isolated a human genomic clone, and sequenced the promoter of this gene. By in situ hybridization we have mapped the gene encoding the p50 subunit of NF-kappa B to the 4q23-4q25 region of the human genome and the H1-H3 region of the murine chromosome 3. The p50 promoter lacks TATA and CAAT elements, but contains NF-kappa B, AP-1 and HIP-1 binding sequence. The kappa B motif binds NF-kappa B, KBF1, and heterodimers of p50 and c-rel, suggesting that the gene is regulated by members of this family. Co-transfection experiments demonstrate that the p50 promoter can be activated by either of the two subunits of NF-kappa B (p50 and p65), and more strongly by the combination of both. The promoter of p50 can be activated by phorbol esters and tumor necrosis factor alpha but not by forskolin and these responses are mediated through the NF-kappa B binding sequence. The involvement of NF-kappa B in the regulation of the p50 gene is also supported by the inhibition of the PMA activation of the promoter by an NF-kappa B transdominant negative mutant, as well as the product of the v-rel oncogene.

Animals↗
PubMed1992

Heteroconjugate antibodies enhance cell-mediated anti-herpes simplex virus immunity in vivo.

Heteroconjugate antibodies are generated by covalently linking two mAbs with different specificities. When anti-CD3 mAb, capable of activating effector T cells, is coupled to anti-herpes simplex virus (HSV) mAb, which binds HSV antigens on virally-infected target cells, the resulting heteroconjugate antibody can be used in vitro to enhance anti-HSV immunity. Specifically, these heteroconjugate antibodies can augment anti-HSV immunity among lymphocytes previously lacking cytotoxicity against HSV-infected target cells. However, the efficacy of these specialized reagents in enhancing anti-HSV immunity in vivo has not been determined. We report here that anti-HSV heteroconjugates used in an adoptive transfer murine model of HSV-1 infection inhibited HSV replication in vivo and improved long-term survival. These results demonstrate that heteroconjugate antibodies have a potential therapeutic role in enhancement of anti-HSV immunity.

Animals↗
PubMed1992

Antibody response to cytomegalovirus (CMV) polypeptides in liver transplant recipients with CMV hepatitis.

Immunoblotting (IB) was used to detect the presence of serum antibody against each individual CMV structural polypeptide and the major nonstructural antigen during CMV hepatitis in 12 orthotopic liver transplant recipients to evaluate the diagnostic utility of this technique. The basic phosphoprotein p150 primarily, and to a much lesser extent p65 (lower matrix protein) and p52 (nonstructural DNA-binding protein) were the most recognized antigens by both IgG and IgM class antibodies. Collectively, IgM antibodies were detected to p150 in 9 of 12 (75%) patients and were detected before (2 cases), at the same time (1 case), or after (6 cases) detection of virus in cell cultures. IB was equal to indirect immunofluorescence (IIF) and enzyme immune assay (EIA) for the detection of IgG and superior to EIA for IgM class antibodies to CMV in OLT patients. Our results indicate that the p150 phosphoroprotein is an essential component of serologic assays, especially for the detection of IgM antibodies to CMV.

Antibodies, Bacterial↗
PubMed1991

Modulation of T-cell activation through protein kinase C- or A-dependent signalling pathways synergistically increases human immunodeficiency virus long terminal repeat induction by cytomegalovirus immediate-early proteins.

By using human CD4+ lymphoblastoid T cells transiently cotransfected with human immunodeficiency virus (HIV) and cytomegalovirus (CMV), we tested whether modulation of T-cell activation through the protein kinase C (PKC) or the protein kinase A (PKA) pathway synergized with CMV immediate-early (IE) proteins in HIV long terminal repeat (LTR) transactivation. Stimulation with phorbol myristate acetate, tumor necrosis factor, or cross-linked antibodies to CD3 and CD28 resulted in modest enhancement (two- to fourfold) of the activity of a luciferase expression vector under control of the HIV LTR. Cotransfection of a vector expressing the CMV IE1 and IE2 proteins under the control of their own promoter enhanced HIV LTR activity 16- to 49-fold. Combination of any one of the above stimuli and CMV IE expression amplified HIV LTR activity 99- to 624-fold. Stimulation of PKA-dependent pathways with forskolin, 8-bromo cyclic AMP, or prostaglandin E2 had a minimal effect on HIV LTR activity, whereas such stimuli resulted in synergistic amplification in cells cotransfected with CMV IE (three- to fivefold increases over the effects of CMV IE alone). This synergism was independent of the NF-kappa B binding motifs within the HIV LTR. CMV IE2, but not IE1, protein induced HIV transactivation and synergized with signals modulating T-cell activation. The intense synergism observed was superior to the increase in IE protein expression following PKC activation by phorbol myristate acetate. Treatment of cells with PKC inhibitor GF109203X blocked most of the observed synergism.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1990

Alternative mechanisms of natural killer cell activation during herpes simplex virus infection.

Although NK cells can kill both malignant cells and virus-infected cells without prior sensitization, it has remained unclear whether the mechanism by which an NK cell is activated in the presence of a tumor cell is similar to that induced by the presence of a virus-infected cell. In our experimental system using homogeneous populations of cloned human CD16+ NK cells, we found that HSV-infected target cells do not induce in the NK cells the same pharmacologically-active second messengers elicited by NK-sensitive tumor cells. Although phosphoinositide turnover and calcium signaling were generated in NK cells exposed to NK-sensitive tumor cells, the recognition of HSV-infected cells by NK cells did not result in similar transmembrane signaling. Furthermore, depending on the cell type infected by HSV, alternative mechanisms of cytotoxicity were employed. HSV-infected foreskin fibroblasts were rapidly and selectively killed by cloned NK cells without a requirement for IFN or accessory cells. In contrast to this direct cytotoxicity against HSV-infected foreskin fibroblasts, NK cell-mediated cytotoxicity against an HSV-infected fibrosarcoma cell line (1591) was dependent on IFN-alpha production by accessory cells. Importantly, in both systems of cytotoxicity, IFN-alpha activation of NK cells resulted in augmented killing against both infected and uninfected targets. These results suggest that NK cell activation induced during antiviral immunity is distinct from activation elicited during an antitumor response. These differences include the utilization of alternative forms of signal transduction and alternative mechanisms of cytotoxicity.

Antigen-Presenting Cells↗
PubMed1990

Early diagnosis of cytomegalovirus hepatitis in liver transplant recipients: role of immunostaining, DNA hybridization and culture of hepatic tissue.

Immunostaining techniques that use a monoclonal antibody against an early cytomegalovirus antigen or a polyclonal antibody, in situ DNA hybridization and inoculation of cell cultures for the detection of cytomegalovirus from liver biopsy specimens were studied in 20 liver transplant patients with cytomegalovirus hepatitis, as defined by histological criteria. A total of 108 liver biopsy specimens from 20 patients with a diagnosis of cytomegalovirus hepatitis (obtained per protocol at 7, 21, 90, and 180 days or whenever liver dysfunction occurred), which had previously been examined histologically and in cell culture, were again studied by recutting the liver tissue for histological examination, DNA hybridization and immunostaining with monoclonal or polyclonal antibodies to cytomegalovirus. In 5 of 20 patients, the diagnosis of cytomegalovirus hepatitis could have been made earlier (mean = 9.6 days) by immunostaining with a monoclonal antibody. Of 47 biopsy specimens with cytomegalovirus inclusion bodies, the sensitivity and specificity of the diagnostic procedures were immunostaining with monoclonal antibody (84% and 90%) and polyclonal antibody (72% and 97%), in situ DNA hybridization (72% and 100%) and cell culture detection (52% and 95%), respectively. Immunostaining with a monoclonal antibody against an early CMV antigen frequently detected cytomegalovirus infection in the liver allograft earlier than identification of typical histological inclusion bodies. DNA in situ hybridization was less sensitive than other techniques but highly specific; cytomegalovirus cell culture lacked sensitivity compared with the other procedures.

Adult↗
PubMed1990

Inhibition of Theiler's virus-induced demyelination in vivo by tumor necrosis factor alpha.

Employing a murine model of multiple sclerosis which utilizes intracranial injection of Theiler's virus murine encephalomyelitis (TMEV) into SJL/J mice, we tested the potential role of tumor necrosis factor alpha (TNF-alpha) in ameliorating CNS demyelination. Infection with TMEV caused early grey matter inflammation (7 days post-infection) in the brain and spinal cord followed by chronic demyelination (35 days post-infection) in the spinal cord. Administration of recombinant human or mouse TNF-alpha starting 12 h prior to infection and then three times weekly had minimal effect on development of grey matter inflammation in the spinal cord. In contrast, TNF-alpha dramatically reduced demyelination present in spinal cord on days 14 and 35 after TMEV infection (P less than 0.01) when compared to controls. CNS virus titers of TMEV were not modified by TNF-alpha administration as measured on days 7, 14, and 35 following infection. In vivo administration of TNF-alpha inhibits TMEV-induced demyelination in susceptible SJL/J mice without affecting virus replication in the CNS.

Animals↗
PubMed1989

Role of natural killer cells as immune effectors in encephalitis and demyelination induced by Theiler's virus.

Infection of susceptible mice (SJL) with Theiler's murine encephalitis virus (TMEV) causes a biphasic disease characterized by gray matter inflammation followed by late chronic demyelination. The role of NK cells was studied in this model by using susceptible (SJL) or resistant (C57BL/10) mice. CNS TMEV titer were higher in SJL compared with C57BL/10 mice, correlating with a 50% lower NK cell activity in the SJL than in the C57BL/10 mice. When resistant (C57BL/10) mice were depleted of NK cells using either mAb NK1.1 or polyclonal anti-asialo-GM1, TMEV induced the development of diffuse encephalitis and meningitis early in the postinfection period (days 6 to 11). However, the second phase of TMEV-induced CNS disease (demyelination) was observed only in resistant C57BL/10 mice treated with anti-asialo-GM1. Experiments with beige/beige mice of C57BL/10 background showed a mild degree of gray matter inflammation but no demyelination. In conclusion, NK cells are critical effectors in protecting against TMEV-induced gray matter disease, whereas a different population of either NK1.1- NK cells, or other activated lymphocytes may be critical in resistance/susceptibility to demyelination.

Animals↗
PubMed1989

Heteroconjugate antibodies enhance cell-mediated anti-herpes simplex virus immunity.

Impaired cell-mediated immunity predisposes individuals to severe systemic HSV infections. A potential approach for enhancing antiviral immunity is to alter the specificity of T cells and NK cells so that they become cytotoxic against HSV. We describe here the use of heteroconjugate antibodies to augment the killing of HSV-infected cells. Two different types of heteroconjugate antibodies were used: 1) CD3-specific mAb, covalently linked to HSV-specific mAb (e.g., anti-CD3 x anti-HSV-1 glycoprotein C); 2) FcR-specific mAb linked to HSV-specific mAb (e.g., anti-Fc gamma RIII x anti-HSV-1 glycoprotein D). Whereas freshly isolated, PBL were not cytotoxic against HSV-infected target cells in a 5-h 51Cr-release assay, co-incubation with either heteroconjugate resulted in significant cytotoxicity. In vitro activated PBL (anti-CD3 + IL-2) also became more potent killers of HSV-infected cells in the presence of each heteroconjugate. The specificity of anti-CD3 x anti-HSV-1 and anti-Fc gamma RIII x anti-HSV-1 gD for enhancing T cell and NK cell immunity, respectively, was confirmed by using cloned, homogeneous human T cell and NK cell lines as effectors. Kinetic analysis demonstrated that as soon as the infected cells began to express HSV glycoproteins on their surface they became susceptible to this enhanced killing. Prolonged culture of HSV-infected cells with heteroconjugate antibodies and effector cells also decreased the amount of viral replication that occurred, as measured in a plaque inhibition assay. These results suggest that heteroconjugate antibodies are potent immunotherapeutic tools that enhance anti-HSV immunity.

Adjuvants, Immunologic↗
PubMed1989

T-cell non-Hodgkin lymphoma in human immunodeficiency virus-1-infected individuals.

We present two patients with human immunodeficiency virus-1 (HIV-1) infection in whom T-cell non-Hodgkin lymphoma developed, based on pathologic diagnosis, immunophenotyping, and T-cell receptor gene rearrangement. Both cases were positive for human immunodeficiency virus-1 by enzyme-linked immunosorbent assay and immunoblot methods. Histologic sections from each patient showed a high-grade pleomorphic T-cell non-Hodgkin lymphoma, and immunophenotyping demonstrated a prevalence of reactivity for CD4 (helper) over CD8 (suppressor) antigens. T-cell receptor beta-chain gene rearrangement studies revealed a rearranged pattern with either the HindIII or BamHI enzymes, whereas immunoglobulin heavy chain genes retained a germ-line configuration. Viral sequences specific for human T-cell leukemia virus-I, human T-cell leukemia virus-II, or HIV-1 were not detected. Thus, although rare, T-cell non-Hodgkin lymphoma may be observed in HIV-1-infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Bacterial infections after liver transplantation.

Infection is a common complication of orthotopic liver transplantations and a major cause of mortality. Of the different types of infection, severe bacterial infections are the most common. The majority (81%) of bacterial infections occur within the first two months after liver transplantation. The most frequent site of infection is the abdomen (intrahepatic or extrahepatic abscesses, cholangitis, and peritonitis). Bacteremia is a marker of mortality, and the majority of bacteremia cases are secondary to another bacterial infection site. The causative organisms vary among different centers. In some, gram-negative organisms are more common (66%); in one center, however, gram-positive microorganisms predominate (66%). In the latter center, the use of nonabsorbable antibiotics, which eradicate gastrointestinal aerobic gram-negative microorganisms, may explain this microbiologic difference. The main risk factor predisposing to bacterial infection appears to be the duration of the transplantation operation, especially beyond 12 hours. Of the deaths resulting from infection, 81% were caused by bacterial infection.

Abscess↗
PubMed1989

Rapid shell vial culture and tissue histology compared with serology for the rapid diagnosis of cytomegalovirus infection in liver transplantation.

Sixty-six patients who had undergone 78 liver transplantations, with no detectable cytomegalovirus (CMV) infection before transplantation, were studied to assess the value of CMV serology compared with the rapid detection of the virus in shell vial cell cultures or histology for the diagnosis of (1) the first evidence of infection, (2) symptomatic disease, and (3) asymptomatic infection. Of 28 evaluable patients, shell vial cell culture assay and histologic findings provided the first evidence of CMV infection earlier in 22 (79%) or at the same time as the serologic response in 5 (18%). Serologic results yielded the first indication of CMV infection in only 1 of these 28 patients (3%). Of 17 evaluable transplantations in 15 patients in whom symptomatic invasive disease developed, shell vial culture or histology provided a laboratory diagnosis of CMV infection earlier or at the same time as serologic responses in 16 (94%). Similarly, shell vial culture or histology provided evidence of CMV infection in 10 of 11 patients (91%) who had asymptomatic CMV infection and remained asymptomatic. Urine surveillance cultures yielded the first evidence of CMV infection in 14 of 19 patients who initially had an asymptomatic infection, of which 6 became symptomatic. Culturing of the blood with use of the rapid shell vial technique showed that viremia preceded CMV organ involvement in 7 of 10 patients. We recommend culture by the shell vial assay as the most rapid and sensitive method of determining CMV infection in liver transplant patients.

Cytomegalovirus Infections↗
PubMed1989

Incidence, distribution, and outcome of episodes of infection in 100 orthotopic liver transplantations.

Of 83 patients who underwent 100 orthotopic liver transplantations, 53 had a single transplant procedure and at least 6 months of follow-up. In this main study group of 53 patients, major infections developed in 28 (53%) (a mean of 1.8 major episodes per infected patient). Of 51 major infections, 27 were bacterial, 19 were viral, 3 were protozoan, and 2 were fungal. Of the 27 bacterial infections, 22 (81%) occurred in the first 2 months after transplantation. Of the 40 bacterial isolates in the 27 bacterial infections, gram-positive aerobic bacteria were isolated in 26 (65%), anaerobic bacteria in 8 (20%), and aerobic gram-negative bacteria in 6 (15%). Only 1 of 16 bacteremic episodes was due to a gram-negative aerobic bacterium. Cytomegalovirus (CMV) infection occurred in 30 of the 53 patients (57%) and was symptomatic and invasive in 18. CMV infection was diagnosed a mean of 26 days after transplantation. Infections due to Pneumocystis carinii occurred later (2 to 3 months after transplantation). Death from infection occurred in 4 of the 53 patients (8%). In the group of 16 patients with two or more liver transplantations, fungal infection occurred in 2 and CMV infection in 13. In all 16 patients who underwent more than one liver transplantation, a major infection developed. The observations made in the main study group were consistent with findings in 13 patients with one liver transplantation but less than 6 months of follow-up. Infection is a major complication after liver transplantation, generally occurring in the first 2 months. Our observations suggest that the use of selective bowel decontamination may be associated with a relatively lower incidence of gram-negative aerobic bacterial infections.

Bacterial Infections↗
PubMed1989

Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations.

Ninety-three consecutive orthotopic liver transplantations in 78 patients were followed prospectively to study the incidence of cytomegalovirus (CMV) hepatitis. CMV hepatitis occurred in 13 (17%). The diagnosis was established by both histology and culture in 5, only by histology in 6, and only by culture in 2. All 13 patients had CMV viruria and 9 had viremia at diagnosis. CMV hepatitis developed in 64% of CMV-seronegative (pretransplantation) patients who received a liver from a CMV-seropositive donor, compared with 3% or 6% of CMV-seropositive patients who received a liver from a CMV-seronegative or CMV-seropositive donor, respectively (P less than .001). CMV hepatitis was not a cause of fulminant or irreversible liver dysfunction in any of the 13 cases. Ganciclovir was administered to 6 of the 13 patients and was associated with clinical and virologic cure in 5. CMV hepatitis was self-limited in patients not treated with ganciclovir (illness less severe). The presence of inclusions within the liver tissue correlated with active disease.

Age Factors↗
PubMed1989

Limited usefulness of quantitative culture of blood drawn through the device for diagnosis of intravascular-device-related bacteremia.

The use of a differential quantitative blood culture technique (Isolator) to diagnose intravascular-device-related bacteremia (IDRB) was studied prospectively. During septic episodes in 44 patients, blood was obtained simultaneously through the suspected infected device and from a peripheral venipuncture. The blood samples were processed by the Isolator technique, which enables easy quantification of microorganisms. The cannula was removed, and its tip was cultured semiquantitatively. Of the 52 cannulas studied, 15 were the cause of IDRB, but only 7 of these showed a significantly higher bacterial count in blood obtained through the device compared with peripheral blood. The bacterial count was higher in blood drawn through the device than in peripheral blood in four of six cases that did not fulfill the definition of IDRB. Some blood cultures obtained through the device were positive despite negative cultures of peripheral blood and cannula tips (six cannulas). Quantitative blood cultures were not useful in diagnosing IDRB in this study.

Adult↗