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Biomedical subjects

M A Epstein

Publications and source records attributed to M A Epstein.

At least 55 records · Page 3Linked to original sources
PubMed1985

A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals.

A panel of 24 healthy seropositive donors have been followed prospectively over a period of 15 months and monitored (1) for the level of EB virus shedding in the throat by means of a sensitive cord-blood transformation assay; (2) for the level of virus-infected B cells in the blood via a new in vitro protocol where "spontaneous transformation" can be seen to titrate against input cell number; (3) for anti-EB viral antibody titres and (4) for the prevailing level of virus-specific memory T cells in the circulation. Six donors shed easily detectable levels of EB virus into throat washings on every occasion of testing, whilst 16 other donors shed lower levels of virus detectable in throat washings on a majority (10 donors) or on a minority (6 donors) of test occasions; only 2/24 donors gave no evidence of virus shedding at any time. There was a direct relationship between the EB virus shedder status of an individual (i.e., the level of virus replication in the pharynx) and the number of infected B cells present in the circulation. These results indicate that chronic, usually low-grade, replication of the virus at some permissive site in the oro- and/or naso-pharynx is very often a stable accompaniment of the asymptomatic EB virus carrier state, and may indeed be essential for the long-term maintenance of that state.

Adult↗
PubMed1985

In vitro analysis of the Epstein-Barr virus: host balance in long-term renal allograft recipients.

Four indices of the EB virus carrier state, for which quantitative in vitro assays now exist, have been monitored in 55 renal allograft recipients under long-term immunosuppression, each patient being tested on a single occasion. By comparison with parallel data from healthy control donors, the results indicate the extent to which virus replication in the throat and virus-infected B cells in the blood are increased as a result of immunosuppression; the concordance between these two independent indices of the level of EB virus infection in vivo, first noted with healthy donors, was again observed within this large group of patients. Immunosuppression also leads to an impairment of virus-specific memory T-cell responsiveness and to an increase in anti-viral antibody titres, but the results show that the level of virus infection prevailing in any one individual cannot be inferred directly from these immunological indices of the virus:host balance. In allograft patients on stable levels of immunosuppression, virus and host appear to establish a new equilibrium. Limited prospective studies suggest that the position of this new equilibrium depends critically upon the virus:host balance prevailing in the same individuals before immunosuppression began. This may be an important consideration in identifying patients for whom immunosuppression may carry a particularly high risk of developing EB virus genome-positive lymphoma.

Adult↗
PubMed1985

Allospecific T cell recognition of HLA-A2 antigens: evidence for group-specific and subgroup-specific epitopes.

Interleukin 2-dependent alloreactive cytotoxic T cell lines, with activity predominantly directed against the HLA-A2 antigen, have been generated in vitro by stimulating blood mononuclear cells from donors nonimmune to the Epstein-Barr (EB) virus with appropriate numbers of EB virus-transformed B cells from A2-homozygous individuals. Such effector cells were tested against a panel of EB virus-transformed target cell lines all expressing the serologically defined A2 antigen but typed into "common A2" and "variant A2" subgroups on the basis of their recognition by A2-restricted EB virus-specific cytotoxic T cells. "Variant A2" responder cells cocultivated with "common A2"-bearing stimulators gave rise to effector T cell lines which recognized only the "common A2"-bearing subgroup of targets. By contrast, responder cells from A2-negative donors stimulated with "common A2"-bearing cells produced effector T cell lines in which the strong lysis of "common A2"-bearing targets was accompanied by a lower, but still significant, lysis directed against all targets within the "variant A2" subgroup. In both cases, lysis of the target cells was blocked equally well by the anti-A2-specific monoclonal antibody MA2.1 as by the monoclonal antibody W6/32 specific for HLA-A, -B, and -C determinants. This suggests that HLA-A2 molecules possess at least two distinct sets of epitopes capable of inducing alloreactive T cell cytotoxicity: first, epitopes probably associated with T cell-restricting sites, which generate subgroup-specific responses, and second, epitopes shared by all A2 molecules, and perhaps associated with serologically defined sites, which generate "pan A2" group-specific responses.

B-Lymphocytes↗
PubMed1985

The role of HLA antigens in the control of the cytotoxic T-cell response to Epstein-Barr virus: a family study.

Epstein-Barr (EB) virus-specific, HLA-restricted cytotoxic T-cell populations have been generated in vitro from each member of a family by cocultivating peripheral blood mononuclear cells with autologous EB virus-transformed B cells, the resulting effector cells being expanded as interleukin 2-dependent T-cell lines. The cytotoxicity of each of these effector populations was tested on a large panel of EB virus-transformed target cells of known HLA type, so that the particular HLA antigens which acted as restricting elements for each cytotoxic population could be identified. There was a consistent pattern within the family of preference for certain HLA class I antigens as restricting elements of the virus-specific T-cell response. Extensive functional analysis showed that, in addition to the virus-specific lysis, each effector population mediated a cross-reactive lysis against target cells prepared from certain HLA-mismatched individuals. This cross-reactivity appeared to be directed against HLA class I alloantigens and occurred irrespective of the EB virus genome status of the target cells. Effector T-cell lines derived from different family members but with virus-specific lysis predominantly restricted through the same HLA antigen showed similar patterns of concomitant allo-cross-reactivity. This suggests that antigenic mimicry of virally altered self by alloantigens is a genuine phenomenon which may be important in channelling the human cytotoxic T-cell response to a virus through preferred self-HLA determinants.

Cell Line↗
PubMed1985

Soda lime adsorption of isoflurane and enflurane.

The authors demonstrated that soda lime will adsorb enflurane or isoflurane as a function of the water content of the soda lime. Various volumes of liquid enflurane or isoflurane were placed in an equilibration flask containing fresh (15% water by weight) or dried soda lime and the vapor phase anesthetic concentrations plotted. When dry soda lime was used, the plot of concentration as a function of volume of liquid added was biphasic: initially flat and then rising linearly. This is qualitatively similar to data reported previously for halothane. The authors hypothesize that drying soda lime produces a molecular sieve-like structure, as adsorption is greatest for molecules with small carbon chain lengths and kinetic diameters, or with structural characteristics such as cis/trans isomerism, which effectively reduce molecular size.

Adsorption↗
PubMed1985

Model studies on distributions of blood cells at microvascular bifurcations.

To model the flow behavior of white and red blood cells at microvascular branch points, the distribution of neutrally buoyant spherical and disk-shaped particles at a symmetric T bifurcation was investigated for low Reynolds number flows (0.01-0.1). The particle distribution was represented by the fractional particle flux to a daughter branch as a function of the fractional volumetric bulk flow to the same branch. Particle-to-tube diameter ratios of 0.32-0.79 were studied for the spherical particles and 0.4-0.8 for the disks. As the particle dimensions approach that of the tube, the relation between the fractional particle flux and fractional bulk flow changes from a linear relation of unity slope to a nonlinear S-shaped curve. Measurements of the flow divider at the entrance to the bifurcation and the eccentricity distributions for the spheres and disks were used to develop a model that permits prediction of the observed particle distributions. These results can be used to interpret the distribution of white and red blood cells in microvascular bifurcations with dimensions close to the cell size.

Blood Cells↗
PubMed1985

Rearing a second generation of cotton-top tamarins (Saguinus oedipus oedipus) in captivity.

The average age at first parturition in captive-born female cotton-top tamarins was 31 months. Only 18% of full-term young born were successfully reared by primiparous females, but success increased with parity and 71% of babies born at 4th and 5th pregnancies were raised. 15% of litters were single births, 61% were twins and 24% were triplets. There was a seasonal distribution of births, with a clear peak in the spring months. The average interbirth interval was 294 days.

Animals↗
PubMed1985

Cell-mediated immunosurveillance mechanisms and the pathogenesis of Burkitt's lymphoma.

Paired Epstein-Barr virus (EBV)-carrying cell lines have been established from Burkitt's lymphoma (BL) patients, one of each pair being the BL cell line derived from the malignant cells of the tumour, the other, the lymphoblastoid cell line (LCL) derived from the patient's normal B cells by experimental infection with the virus. Comparative studies have shown the following: (1) All the lines were to some extent sensitive to in-vitro activated natural-killer cells, individual pairs differing as to whether BL or LCL cells were more susceptible. (2) For six of the seven pairs tested, the BL cell line was clearly sensitive to allo-specific (anti-class 1 HLA) effector T cells, although levels of lysis were slightly below those observed for the corresponding LCL; only one BL cell line showed evidence of a dramatic reduction of HLA antigen expression, and this line was insensitive to allo-specific cytolysis. (3) For two of the three pairs tested to date, EBV-specific cytotoxic T-cell preparations from HLA antigen-matched donors lysed the LCL but not the BL cell line, despite the latter's apparent expression of the relevant restricting antigens. In both of these cases, it was known that the tumour arose in vivo in the face of prevailing EBV-specific T-cell surveillance. An escape of the malignant cells from such surveillance may therefore be important in the overall pathogenesis of EBV genome-positive BL.

Burkitt Lymphoma↗
PubMed1984

Paired Epstein-Barr virus-carrying lymphoma and lymphoblastoid cell lines from Burkitt's lymphoma patients: comparative sensitivity to non-specific and to allo-specific cytotoxic responses in vitro.

Paired Epstein-Barr (EB) virus-carrying cell lines have been established from Burkitt's lymphoma (BL) patients; one the BL-cell line derived from the malignant cells of the tumour and bearing the relevant chromosomal translocation, the other the diploid lymphoblastoid cell line (LCL) derived from the patient's normal B cells by experimental infection with the virus. Comparative studies have shown that both BL and LCL cells are relatively resistant to fresh NK cells but are more susceptible to in vitro-activated NK cells; individual pairs differ as to whether the BL or LCL cells are more sensitive to such effectors. With most cell pairs studied, the two cell types were equally efficient at inducing NK-cell activation in vitro. When the in vitro stimulation protocol was changed to favour the induction of allo-specific responses, most BL cells were noticeably poorer stimulators than the corresponding LCL although both cell types induced a similar pattern of cytotoxicity; this appeared to be directed against HLA class I allo-antigens and could be inhibited by class I antigen-specific monoclonal antibodies. Most BL target lines, though susceptible to this allo-specific lysis, were significantly less so than the corresponding LCL However, only 1/7 BL-cell lines tested vis-à-vis the LCL gave evidence of a gross reduction in HLA antigen expression and this was immediately apparent from both serological typing and cellular analysis.

Burkitt Lymphoma↗
PubMed1984

The Leeuwenhoek lecture, 1983. A prototype vaccine to prevent Epstein-Barr virus-associated tumours.

EB virus is a herpesvirus that infects all human communities. The infection is life-long and usually asymptomatic. Excessive reaction to primary infection leads to infectious mononucleosis while immunological failures give fatal lymphoproliferative diseases. The virus is associated with endemic Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma. In world cancer terms Burkitt's lymphoma is insignificant, but nasopharyngeal carcinoma has a high incidence in certain important populations. By analogy with herpesvirus-induced animal cancers, prevention of infection should greatly reduce subsequent development of tumours. A prototype vaccine has therefore been produced based on the virus-determined antigen (MA gp340) that elicits virus-neutralizing antibodies. A sensitive assay has permitted the elaboration of an efficient antigen preparation method and the product has been rendered highly immunogenic, as tested in mice and rabbits, by incorporation in liposomes. The only animal suitable for experimental EB virus infection is the little-known cottontop tamarin; a breeding colony has been successfully established and protection against virus challenge assessed in immunized tamarins. The overall structure of the antigen has been determined in preparation for future production by synthesis or rDNA technology.

Animals↗
PubMed1984

Comparative immunogenicity studies on Epstein-Barr virus membrane antigen (MA) gp340 with novel adjuvants in mice, rabbits, and cotton-top tamarins.

The effectiveness of immunisation of mice, rabbits, and cotton-top tamarins with small amounts of EB virus MA glycoprotein gp340 , incorporated into artificial liposomes, has been compared using various routes of injection with or without additional adjuvants. Liposomes containing gp340 gave specific high titre antibodies after i.p. or i.v. administration, and the addition of lipid A to the liposomes resulted in a significant enhancement of the response. Antibodies generated by the above procedure were virus neutralising and bound gp340 specifically. These findings indicate an advantageous approach for use with a prototype vaccine for the prevention of EB virus infection.

Adjuvants, Immunologic↗
PubMed1984

Mutant HLA-A2 antigens as restricting elements for virus-specific cytotoxic T cells.

Mutants of the EB virus-transformed cell line T5-1 (HLA-A1, 2; B8, 27), bearing well-characterized alterations in HLA-A2 antigen expression and unable to bind the HLA-A2-specific monoclonal antibody BB7.2, have been tested for their susceptibility to EB virus-specific cytolysis using effector T-cell preparations functionally restricted through relevant HLA antigens. Initial experiments first confirmed that the parent line T5-1 was susceptible to cytolysis by both "common" A2-restricted and B27-restricted effector cells. While those T5-1 mutants with little or no surface A2 expression were not lysed by A2-restricted effectors, those targets with quantitatively normal expression of mutant A2 molecules were as susceptible to A2-restricted lysis as the parent line itself. In contrast, all the T5-1 mutant lines were susceptible to B27-restricted cytolysis. The results demonstrate that experimentally induced mutations of HLA-A2 antigen structure, affecting a serologically defined site on the molecule, can occur without altering that same molecule's expression of the T cell-restricting determinant(s). Such experimentally induced mutations are quite different from the naturally occurring "variant" A2 antigens which are present within the serologically defined A2 antigen group and which show changes at the T cell-restricting site.

Antibodies, Monoclonal↗
PubMed1984

T-cell-mediated regression of "spontaneous" and of Epstein-Barr virus-induced B-cell transformation in vitro: studies with cyclosporin A.

The regression of Epstein-Barr (EB) virus-transformed B-cell outgrowth which is seen in experimentally-infected cultures of blood mononuclear (UM) cells from healthy seropositive donors can be abolished in medium containing the T-cell-suppressive agent cyclosporin A (CSA) at concentrations of 0.05 microgram/ml and above. CSA mediates its effect within the first 4 days post-infection of the UM cells and this prevents subsequent in vitro generation of the EB virus-specific cytotoxic-T-cell response which normally brings about regression. Regression can be fully restored by supplementing the CSA-treated culture with interleukin 2 (IL-2)-containing culture supernatants or indeed with purified IL-2 itself, suggesting that CSA mediates its effect in this system through inhibiting the endogenous production of IL-2 which is required to amplify the virus-specific cytotoxic response. "Spontaneous transformation" to EB virus genome-positive lymphoblastoid cell lines in noninfected cultures of UM cells from healthy seropositive donors, though rare in normal medium, is enhanced to such a degree in the presence of CSA that, for many donors, the phenomenon becomes titratable against input cell dose across the 2.0 X 10(6)-2.5 X 10(5) cells/culture range. Cell mixing experiments suggest that the spontaneously transformed cell lines which arise with such efficiency under these conditions do so not by direct in vitro outgrowth of progenitor cells transformed by the virus in vivo, but by a two-step mechanism involving virus release and secondary infection in vitro.

B-Lymphocytes↗