Detection of immunosuppressive early pregnancy factor in humans.
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Chaperonin 10↗
Biomedical subjects
J Menezes
Publications and source records attributed to J Menezes.
Isoprinosine abolishes the blocking factor-mediated inhibition of lymphocyte responses to Epstein-Barr virus antigens and phytohemagglutinin.
Acute infectious mononucleosis (IM) is accompanied by measurable abnormalities of immune function, including a transient immunosuppression. The sera of patients with acute IM contain an IgG blocking factor which binds to T-lymphocytes and decreases their responses to antigens and mitogens. The experiments reported herein indicate that isoprinosine, an immunopotentiating agent, can reverse this inhibition of T cells by IM-associated IgG blocking factor. Isoprinosine may be a useful tool in understanding the interactions between blocking factors and lymphocytes; moreover, isoprinosine may be of value in patients with abnormal clinical responses to Epstein-Barr virus (EBV) such as chronic IM or persistent active EBV infections.
Antigens, Viral↗
Generation of Epstein-Barr virus antigen-specific suppressor T cells in vitro.
Immunosuppression is a commonly observed phenomenon in Epstein-Barr virus (EBV)-associated disorders and malignancies. The purpose of this study was to determine whether EBV antigens could generate suppressor cell activity in vitro. Peripheral blood lymphocytes (PBL) were first treated with various concentrations of EBV antigens or culture medium for 5 days and then with mitomycin C. The cells were then washed and tested for their ability to abrogate the blastogenic response of fresh, autologous PBL to previously determined optimal concentrations of EBV antigens. It was found that excess of both EBV antigens tested (soluble antigen and virus particles) induced suppressor cells, while optimal antigen concentrations failed to do so. In addition, PBL incubated with excess of EBV antigens for 10 days, without mitomycin treatment, inhibited the response of fresh autologous lymphocytes to EBV antigens. The generated suppressor cells were found to be antigen-specific since they inhibited the response of sensitized lymphocytes to the inducing antigen only. Moreover, experiments performed using purified lymphocyte subpopulations indicated that the suppressor activity was associated with T-cell populations. Using T-cells specific monoclonal antibodies, we further determined that the inhibitory activity was due to suppressor (OKT 8+) T-lymphocytes; treatment of T-lymphocyte populations (exhibiting suppressor activity) with OKT 8 antibody and complement abrogated the inhibitory effect of these populations on the response of sensitized lymphocytes to EBV antigens. Taken together, these observations suggest that similar suppressor cells may be at least partly responsible for the immunosuppression observed in patients with an antigenic overload, particularly during persistently active virus infection or malignancy.
Adult↗
Instrument failure in in vitro fertilization: a case report.
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Embryo Transfer↗
Isoprinosine enhances the activation of sensitized lymphocytes by Epstein-Barr virus antigens.
Isoprinosine, a synthetic purine derivative and a potentially useful immunostimulating agent, was tested for its ability to enhance lymphocyte responses to Epstein-Barr virus (EBV) antigens and to autologous EBV-transformed lymphocytes. Isoprinosine significantly enhanced the response of sensitized lymphocytes (i.e. from EBV-seropositive individuals) to EBV antigens, while it has no effect on the lack of response of unsensitized lymphocytes (i.e. from EBV-seronegative individuals) to these antigens. In addition, isoprinosine enhanced lymphocytes response to autologous EBV-transformed cells, and potentiated the generation of cytotoxic lymphocytes. From these observations, and since immunosuppression is commonly observed in EBV-associated malignancies and other EBV-induced disorders, it may be important to point out that the use of isoprinosine as an immunostimulating agent in patients with these diseases deserves serious consideration.
Antigens, Viral↗
Relationship between acrosome reaction and in vitro fertilization of zona-free hamster eggs by bonnet monkey (Macaca radiata) spermatozoa.
The relationship between acrosome reaction, as studied by FITC-RCA staining technique, and the penetration of bonnet monkey spermatozoa into zona-free hamster eggs was investigated. The acrosomes of unreacted spermatozoa fluoresced, whereas those of acrosome-reacted sperm did not fluoresce owing to decreased binding of the lectin. The percentage of acrosome-reacted sperm increased following 3 h of incubation in BWW medium. The assessment of acrosome reaction by the FITC-RCA staining technique correlates well with the in vitro fertilization of zona-free hamster eggs.
Acrosome↗
Synthesis and release of plasminogen activator by lymphoid cell lines of malignant origin and its effect on lymphocyte cytotoxicity.
Lymphoid B, T. Null and plasma cell lines of malignant origin were evaluated for their ability to produce plasminogen activator (PA) in the 125I-fibrinolysis assay. These cell lines produced PA at varying extent. PA was detected in cell-free conditioned medium as well as in cell lysates. The fibrinolysis due to PA was dependent on the presence of plasminogen in the medium. PA purified by affinity chromatography not only abrogated cytotoxicity of peripheral blood lymphocytes significantly, but also the lysis of autologous EBV-transformed cells by in vitro generated cytotoxic lymphocytes. These results indicate that PA produced by malignant cells could inhibit host cellular immunity, thus providing the tumor cells with an escape mechanism from host defences.
Burkitt Lymphoma↗
A familial syndrome of susceptibility to chronic active Epstein-Barr virus infection.
In two members of a family (daughter and father) active Epstein-Barr virus (EBV) infections persisted over periods of 4 and 3 years respectively (possibly 10 years in the father). Both had persistent splenomegaly and occasional bouts of unexplained fever but lived otherwise normal lives. The other members of the family (mother and son) were healthy. The titres of antibody to the EBV viral capsid antigen (VCA) and early antigen (EA) were extremely high in the daughter's blood, whereas the titres of antibody to the Epstein-Barr nuclear antigen were low in the daughter's blood and undetectable in the father's. Target cells of the EBV infection that were obtained from the daughter's blood were established in culture with great difficulty and showed increased expression of VCA and EA. Other immunologic investigations in the two patients revealed that the ratio of helper to suppressor T lymphocytes was inverted, natural killer-cell activity was abnormally low, lymphocyte responses to certain mitogens were depressed and there was a serum factor blocking mitogen-induced transformation. The possibility that the patients' unusual susceptibility to EBV infection represented an inherited syndrome (perhaps X-linked) is discussed.
Antibodies, Viral↗
Purified plasminogen activating factor produced by malignant lymphoid cells abrogates lymphocyte cytotoxicity.
Immunosuppression is a generally observed phenomenon in patients with malignancies. Here we report that plasminogen activating factor (PAF) produced by human (P3HR-1) and simian (B95-8) lymphoid cells of malignant origin abrogates lymphocyte cytotoxicity. PAF has been purified from Epstein-Barr (EB) virus genome carrying lymphocyte cytotoxicity. PAF has been purified from Epstein-Barr (EB) virus genome carrying lymphoid lines by affinity chromatography using lysine-Sepharose columns. Purified PAF consistently inhibited Killer cell activity against the following targets: K-562, EB virus superinfected Raji cells and in vitro EB virus transformed autologous B lymphocytes. Furthermore PAF also inhibited the antibody-dependent cellular cytotoxicity. The results presented also indicate that PAF affects the effector lymphocytes and not the target cells. Taken together, these observations emphasize the importance of factors such as PAF, released by malignant cells, as inhibitors/modulators of immune mechanisms effective against tumour cells.
Animals↗
Sendai virus envelopes can mediate Epstein-Barr virus binding to and penetration into Epstein-Barr virus receptor-negative cells.
Epstein-Barr virus (EBV) receptor-negative cells were treated with UV-inactivated Sendai virus (SV) or with reconstituted SV envelopes having a low hemolytic activity and then assayed for EBV binding or for susceptibility to EBV infection. EBV binding was assessed by using both unlabeled and fluoresceinated EBV preparations. It was found that SV or SV envelope treatment renders these cells able to bind EBV. Various experiments were performed to clarify the mechanism of this SV-induced binding. The EBV receptor-negative 1301 cells were treated with SV either at 0 degrees C or at both 0 and 37 degrees C successively and then examined for EBV binding at 0 degrees C. It was thus found that when SV treatment was performed exclusively at 0 degrees C, the target cells showed higher fluorescence intensity after their incubation with fluoresceinated EBV. In addition, Clostridium perfringens neuraminidase treatment of 1301 cells did not induce any EBV binding to these cells. These data indicate that EBV binding is not due to the disturbance of the cell membrane by SV envelope fusion or to the uncovering of EBV binding sites on the cells after the enzymatic action of SV neuraminidase. Moreover, bound EBV was partly eluted from SV-treated 1301 cells at 37 degrees C, and the treatment of EBV with C. perfringens neuraminidase inhibited its SV-mediated binding. These data indicate that EBV binds to the hemagglutinin-neuraminidase of SV on the target cell surface and that a fraction of the bound EBV becomes irreversibly associated with the SV-treated cell membrane. Our data also show that EBV can penetrate into 1301 cells which have incorporated SV envelopes into their membrane, as demonstrated by the induction of the EBV-determined nuclear antigen by B95-8 EBV in SV envelope-treated 1301 cells.
Animals↗
Involvement of macrophage-like cells in growth of tumors induced by avian sarcoma virus.
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Animals↗
Sera from patients with undifferentiated nasopharyngeal carcinoma contain a factor which abrogates specific Epstein-Barr virus antigen-induced lymphocyte response.
A unique association of Epstein-Barr virus (EBV) with the undifferentiated nasopharyngeal carcinoma (NPC) is a well acknowledged phenomenon. We report here the detection of a factor present in the sera of NPC patients which inhibits the blastogenic response of lymphocytes from EBV seropositive individuals to EB virions or soluble antigens. This lymphocyte-stimulation inhibitor (LSI) was found to be associated with the IgA fraction of the serum immunoglobulins. No inhibitory activity was detected in the sera and their immunoglobulin fractions from healthy (both EBV-seropositive and seronegative) individuals and patients with other carcinomas of the head and neck region. Interestingly, the IgA-LSI was absent in the sera of NPC patients who were successfully treated and remained in remission, while it was readily detectable in the sera of NPC patients in relapse, LSI-positive IgA fractions did not inhibit mitogenic response of lymphocytes to phytohemagglutinin. Taken together, the data presented suggest that LSI is a specific inhibitor of the response of sensitized lymphocytes to EBV antigens and that it may indeed represent a marker of great clinical significance regarding undifferentiated nasopharyngeal carcinoma, particularly for its prognosis.
Antigens, Viral↗
Cytotoxic effector cells from infectious mononucleosis patients in the acute phase do not specifically kill Epstein-Barr virus genome-carrying lymphoid cell lines.
We describe a study in which we investigated the cytotoxic activities of thymusderived (T) lymphocytes and natural killer cells against Epstein-Barr virus (EBV) genome-carrying lymphoid cell lines. Purified subpopulations of lymphocytes from eight patients with infectious mononucleosis and six healthy normal EBV-seropositive donors were tested. Enriched T-cells were obtained by passing purified whole blood lymphocyte preparations through human immunoglobulin-anti-immunoglobulin-coated glass bead columns. The cytolytic activity of effector cells was determined by the ability of these cells to lyse human target cells that were internally labeled with (51)Cr. These targets included cells from both EBV genome-carrying and EBV genome-negative lymphoid lines derived from malignant tumors, as well as from lymphocytes transformed in vitro by EBV, and were chosen to represent a wide spectrum of EBV-associated membrane antigens. We found that cytotoxic T-cells from patients with infectious mononucleosis showed no EBV-related specific cell killing per se, although a trend for increased killing of cell lines derived from spontaneous in vivo growing tumors, EBV genome carrying or not, was noted; however, this trend was not observed with cell lines derived from cord blood lymphocytes after EBV infection in vitro. In addition, our data suggest that natural killer cells may play an important role in controlling EBV infection in patients with infectious mononucleosis in the acute phase of the disease, particularly since T-cells (obtained after removal on immunoglobulin-anti-immunoglobulin columns of natural killer cells presumably bearing Fc receptors) were less efficient killers than whole blood lymphocytes; furthermore, lysis by whole blood lymphocytes was also greatest against cell lines derived from malignant tumors (as opposed to in vitro EBV-transformed cord blood lymphoid lines), irrespective of whether these targets were EBV genome positive or negative.
Cell Line↗
Use of fluoresceinated Epstein-Barr virus to study Epstein-Barr virus-lymphoid cell interactions.
As a direct approach to visualize Epstein-Barr virus (EBV) binding to its cellular receptors and to learn more on the nature of this binding, virus preparations were conjugated to fluorescein isothiocyanate and used to detect EBV receptors on lymphoid cells. Different enzymatic and chemical treatments were also applied either to the virus or to target cells or to both, and the effect of these treatments on virus binding was then examined. The results obtained show that: (i) EBV can be fluoresceinated without affecting its infectivity or cell binding ability, and the fluoresceinated virus represents an important tool to investigate the biology and nature of EBV interactions with its cellular receptors; (ii) the two virus strains (P3HR-1 and B95-8) share common receptors on Raji cells; (iii) protease treatment of EBV or target cells abrogates virus binding; (iv) EBV receptors regenerate after removal of the protease, and this regeneration is inhibited by cycloheximide or sucrose; (v) EBV particles bear concanavalin A receptors, and this lectin hinders the interaction of the virus with its cellular receptors; (vi) neuraminidase treatment, various monosaccharides, ovalbumin, and glycopeptides derived from EBV or cell surface do not inhibit virus binding. Taken together, the above data also demonstrate that some cellular and viral surface (glyco-) proteins are required for EBV binding to its targets.
Cell Line↗
Epstein-Barr virus-lymphoid cell interactions. III. Effect of concanavalin A and saccharides on Epstein-Barr virus penetration.
To study some aspects of Epstein-Barr virus (EBV) penetration into target cells, the effect of concanavalin A (ConA) and various saccharides on virus infectivity and cell susceptibility to EBV infection was examined. ConA treatment of the target cells, EBV, or EBV-cell complexes was found to inhibit virus antigen expression. Several control experiments with alpha-d-methyl-mannoside elution of ConA, removal of nonfused EBV particles from the cell surface by trypsin treatment, and addition of ConA at different times postinfection were performed to define the site of ConA action on EBV infection. ConA appeared to have a dual action: (i) it inhibited EBV binding to virus receptors, and (ii) it blocked the penetration of receptor-bound virus into target cells at a trypsin-sensitive stage, thus indicating that ConA prevented the fusion of viral envelope with the target cell membrane. A high sucrose concentration (0.25 M), known to inhibit cell membrane movements, was also found to block EBV penetration at a trypsinsensitive stage, thus suggesting the implication of cell membrane movements and underlying activities (or both) in viral envelope fusion. Lower concentrations of various monosaccharides (0.12 M) did not influence EBV infection. Under conditions of ConA treatment that did not influence EBV infectivity and target cells susceptibility, ConA was able to mediate virus binding to EBV receptornegative cell lines, but no virus antigens were expressed in these cells. These observations reinforced the idea that the mere attachment of EBV to lymphoid cells is not sufficient to lead to infection. In light of the present and previously published data, we postulate the existence of a specific cellular mechanism that allows the penetration of EBV into the target (B) lymphocyte.
Antigens, Viral↗
Epstein-Barr virus (EBV)--lymphoid cell interactions. II. The influence of the EBV replication cycle on natural killing and antibody-dependent cellular cytotoxicity against EBV-infected cells.
We investigated the influence of the Epstein-Barr virus (EBV) replication cycle on natural killing (NK) activity and antibody-dependent cellular cytotoxicity (ADCC) against EBV-infected cells. Peripheral blood lymphocytes from healthy EBV-seropositive and -seronegative donors were separated on Ficoll-Hypaque gradients and used as effector cells in the standard 51Cr release assay to measure NK and ADCC. EBV-genome positive RAJI and DAUDI cells superinfected with either the non-transforming P3HR-1 EBV or the transforming B95-8 EBV were used as targets. The results obtained show that most normal individuals have ADCC and NK activity against P3HR-1 EBV-infected RAJI cells. Both the cytotoxic activities increased with the proportional increase in effector/target (E/T) ratios, assay incubation time, dose of the infecting virus and the time of pre-infection with EBV. Moreover, the data obtained indicate that different immune mechanisms are effective at different stages of the virus replication cycle. During the early stages of virus replication, EBV-superinfected cells are more susceptible to ADCC than to NK, whereas in later stages the susceptibility to NK is increased significantly and appears to play a more dominant role. The nature of the target cells or the strain of EBV used to superinfect these targets did not influence their susceptibility to ADCC and NK activity; however some quantitative differences were found. Using metabolic inhibitors such as cytosine arabinoside, phosphonoacetic acid, actinomycin D, cycloheximide and puromycin, it was found that new DNA synthesis is not essential but some RNA and protein synthesis is necessary, late in the viral cycle, for the superinfected cells to become susceptible to NK and ADCC.
Antibodies, Viral↗
Staphylococcal protein A enhances natural killing activity against lymphoid tumor cell lines.
Protein A (pA), was found to augment the natural killing (NK) activity of peripheral blood lymphocytes against Burkitt's lymphoma-derived Raji and Daudi cells. This pA-enhanced NK activity was determined using the 51Chromium release microcytotoxicity assay. It was found that the increased NK activity was dependent on the concentration of pA used. In addition, the pA-enhanced NK activity was dependent on the time of incubation of pA with the effector and target cell mixture. Pretreatment of effectors for 16 h or more dramatically increased the NK activity against a wide range of tumor targets of different origin and possessing either B, T or null cell surface characteristics. The presence of the Epstein-Barr virus (EBV)-genome in the target cells did not influence the pA-enhanced NK activity. Nylon-wool column-fractionated, non-adherent lymphocytes (enriched in NK cells) showed an increased NK activity in the presence of pA than unfractionated lymphocytes. Pretreatment of certain targets with pA rendered them more sensitive to NK lysis. Interferon production was readily detected in supernatants from cultures of pA-treated effectors or effector-target mixtures, but not in supernatants from pA-treated target cultures tested. Results of different physicochemical treatments indicate that the pA-induced interferon is of gamma type (type II). Thus, the data presented suggest that the pA-induced enhancement of NK activity is most likely mediated by the pA-induced interferon.
Burkitt Lymphoma↗
Epstein-Barr virus (EBV)-lymphoid cell interactions. I. Quantification of EBV particles required for the membrane immunofluorescence assay and the comparative expression of EBV receptors on different human B, T and null cell lines.
We report data on the number of Epstein-Barr virus (EBV) particles required to detect virus binding to target cells (Raji or BJA-B) by means of membrane immunofluorescence (MIF). After determining the optimum conditions for the MIF assay the following aspects of EBV-lymphoid cell interactions were examined: (i) binding of two different strains of EBV to various types of human lymphoid cell lines, (ii) expression of receptors for both EBV and complement on these lines and (iii) induction of EBV-induced nuclear antigen (EBNA) in the different target cells used. The results showed that a minimum of about 2.7 x 10(3) enveloped virus particles/cell were required for an optimum visualization of EBV binding to the target cells tested, and that a lymphoid cell may bear receptors for one prototype strain of EBV but not for the other. A number of cell lines, particularly those of T and null type which express EBV receptors, did not synthesize EBNA, thus indicating that these lines were resistant to EBV infection. Several of these lines, although expressing cell surface EBV receptors, lacked complement receptors.
Antigens, Viral↗