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G Janossy

Publications and source records attributed to G Janossy.

At least 55 records · Page 3Linked to original sources
PubMed1996

Factors that influence activated CD8+ T-cell apoptosis in patients with acute herpesvirus infections: loss of costimulatory molecules CD28, CD5 and CD6 but relative maintenance of Bax and Bcl-X expression.

The expanded CD8+ T-lymphocyte population arising in response to viral infection controls the virus but could also prove damaging to the host unless safely removed at the end of the immune response. Apoptosis provides a mechanism whereby this can be achieved, as apoptotic cells are recognized and engulfed by macrophages. Peripheral blood CD8+ T lymphocytes from individuals with acute viral infections were highly susceptible to apoptosis after short-term culture in vitro. This spontaneous cell death could be prevented by interleukin-2 (IL-2) and was related to a decreased expression of Bcl-2 but not Bax or Bcl-XL, additional molecules that promote or prevent apoptosis, respectively, as well as an increase in CD95. After stimulation with anti-CD3 antibody, T cells from these patients also underwent an activation-induced cell death (AICD) that could not be prevented by IL-2. Interestingly, CD8+ T cells from this patient group expressed lower than normal levels of three costimulatory molecules, CD28, CD5 and CD6, suggesting that stimulation in the absence of a second signal is a possible mechanism for the defective reactivation of these cells. Thus multiple mechanisms, including loss of Bcl-2, increased CD95 and loss of costimulatory molecules, place constraints on the survival and reactivation of activated CD8+ T cells after viral infections. This enables immune activation to be controlled and cellular homeostasis to be re-established during resolution of viral diseases in vivo.

Acute Disease↗
PubMed1995

Staging system for clinical AIDS patients. Royal Free/Chelsea and Westminster Hospitals Collaborative Group.

Although there are wide differences in prognosis between patients with AIDS they are often thought of as a single homogeneous group. We think a simple staging system that accounts for important prognostic factors including type and number of AIDS diseases and the CD4 lymphocyte count is required. We followed 363 AIDS patients at the Royal Free Hospital and reported the occurrence of 680 AIDS-defining diseases (ADDs). We measured CD4 counts at approximately monthly intervals. Severity of AIDS diseases was defined a priori on the basis of survival in the AIDS in Europe study of 6578 AIDS patients: mild-oesophageal candidiasis, Kaposis sarcoma (cutaneous), Pneumocystis carinii pneumonia, extrapulmonary tuberculosis; severe-all other ADDs except lymphoma; very severe-lymphoma. The risk of death increased by 15% (p = 0.08) for each mild condition experienced, by 89% (p < 0.0001) for each new severe condition and by 535% (p < 0.0001) when a lymphoma developed. Estimates from the Cox model were used to derive a score reflecting the risk of death. Patient experience was divided into three categories. Patients in AIDS Grade I had an average death rate of one per 10.1 years, compared with one per 2.8 years in AIDS Grade II and one per 1.1 years in AIDS Grade III. Similar rates were seen in an independent validation study on 1230 AIDS patients at different hospital. Our grading system should be useful for patient management, clinical trial design, surveillance, and resource management.

AIDS-Related Opportunistic Infections↗
PubMed1995

The effect of CMV infection on progression of human immunodeficiency virus disease is a cohort of haemophilic men followed for up to 13 years from seroconversion.

The effect of prior infection with cytomegalovirus (CMV) on progression of HIV disease in a cohort of 111 men with haemophilia was studied after 13 years follow-up. The relative hazards associated with CMV positivity on progression to AIDS, death and a CD4 count of 0.05 x 10(9)/l were 2.28, 2.42 and 2.34, respectively. CMV seropositive patients were significantly older than the seronegative and this was controlled for by using a Cox proportional hazards model. The relative hazards for the three endpoints decreased to 1.89, 1.82 and 1.93 respectively and were marginally non-significant (P = 0.05, 0.08 and 0.08 for the three endpoints respectively). We conclude that this cohort continues to show evidence of a 'co-factor' effect associated with prior infection with CMV which is confounded by age but not completely explained by age differences. The potential biological significance of these results is discussed in the context of recent controlled clinical trials which show a survival benefit from long-term high-dose acyclovir, a drug with activity in vivo against CMV and other herpesviruses.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Bcl-2 protein expression in normal human bone marrow precursors and in acute myelogenous leukemia.

The expression of bcl-2 protein that is involved in preventing apoptosis in hemopoietic and other cells was evaluated by quantitative flow cytometry in various subpopulations in the normal fetal bone marrow (FBM) and in different types of acute myelogenous leukemias (AML). In the FBM the highest bcl-2 levels (mean antibody binding capacity 51 x 10(3) molecules/cell) were found in CD34+ intermediate sized blasts and myeloblasts, while a CD34+ subset of CD10+ lymphoblasts had low bcl-2 content (8-10 x 10(3) molecules/cell) and the CD34-, CD10+ lymphoblasts were, as expected from previous studies, bcl-2- (< 5 x 10(3) molecules/cell). Variable levels of bcl-2 (5.1-222 x 10(3)) were found in 43 tested cases of AML. The bcl-2 levels decrease with granulocytic and monocytic differentiation and, accordingly, cases of AML with M1 and M2 features showed significantly higher mean bcl-2 levels than the leukemias with promyelocytic (M3) or myelo-monocytic (M4/M5) features. Nevertheless, in seven cases of AML the bcl-2 levels were higher than seen in the normal FBM cells and none of these patients remain in remission after 2 years. Furthermore, in several AML cases intraclonal heterogeneity was observed. The undifferentiated smaller blasts with Class-IIdim display had higher bcl-2 content than the more differentiated larger blasts with more granular side scatter and Class-bright expression. In the same subsets of AML blasts the proliferative S-G2-M fractions showed a reciprocal correlation to bcl-2 content. Thus the higher bcl-2 levels may give a survival advantage and confer some degree of drug resistance to the least differentiated blast populations. The multi-parameter analysis described in this paper, including a combined bcl-2 and cytokinetic analysis of phenotypically defined subgroups of AML blasts, may detect early population shifts during relapse and also guide combination drug therapy.

Antigens, CD↗
PubMed1995

Expression of the E2A-PBX1 fusion transcripts in t(1;19)(q23;p13) and der(19)t(1;19) at diagnosis and in remission of acute lymphoblastic leukemia with different B lineage immunophenotypes.

The chromosomal translocation t(1;19)(q23;p13) and its variant form der(19)t(1;19) found in 3-5% of acute lymphoblastic leukemia (ALL) results in the expression of the E2A-PBX1 fusion transcript. Although strongly associated with a pre-B immunophenotype, we report the occurrence of t(1;19) in bone marrow or peripheral blood in nine patients with ALL with the following immunophenotypes: pre-B ALL (four), c-ALL (two), c-ALL clg not tested (one), null-ALL (one) and mature B-ALL (one). The E2A-PBX1 fusion transcript investigated by reverse-transcriptase polymerase chain reaction (RT-PCR) was seen in all patients at diagnosis and/or on follow-up samples. Six patients are alive in first clinical remission. Of these patients, three were PCR+ve from between 2 and 38 months from diagnosis, and three were PCR-ve when examined at 5, 26 and 51 months from diagnosis. Two patients are in second remission. One was PCR+ve at 18 months, suffered a CNS relapse at 21 months but was PCR-ve 1 month later. The other was PCR+ve in remission at 2 and 11 months from diagnosis and in testicular relapse at 31 months, but was PCR-ve 5 months later. The remaining patient died 2 months from diagnosis and was not investigated in remission. The prognostic significance of these findings remains to be investigated.

Adolescent↗
PubMed1995

Presence of CD3+CD8+Bcl-2(low) lymphocytes undergoing apoptosis and activated macrophages in lymph nodes of HIV-1+ patients.

Infection with human immunodeficiency virus 1 causes profound changes in the lymph nodes of infected patients. In particular, large numbers of CD8+CD45RO+ T cells infiltrate both the paracortex and the germinal centers. These cells contained the cytotoxic granule-associated protein TIA-1 but showed no detectable levels of perforin and shared the same characteristics of the expanded, activated, short-lived CD8+ population found during acute viral infections. These cells expressed low levels of Bcl-2 and are likely to be short-lived in vivo as evidenced by the direct observation of CD8+ apoptotic cells in the paracortical areas of the infected nodes. Changes in the paracortical nonlymphoid populations were also seen. There were reactive changes in the blood vessels, and the macrophage population was expanded and activated. Furthermore, apoptotic bodies were seen in the cytoplasm of the activated CD68+RFD-7+RFD-1+ macrophages pointing to the phagocytic capacity of these cells and their role in the clearance of the apoptotic cells from the tissues. These observations suggest that the persistance of CD8+ population in human immunodeficiency virus 1 infection is not a result of the presence of an abnormal CD8+ population but rather a result of an inappropriate over-stimulation of the CD8+ cells.

Adult↗
PubMed1994

Leukemia-associated changes identified by quantitative flow cytometry: I. CD10 expression.

We have compared CD10 antigen expression in normal fetal bone marrow with that of B-linage acute lymphoblastic leukemia (ALL). Both quantitative indirect immunofluoresence (QIFI) and direct immunofluorescence (IF) tests with Quantum beads were used to convert median fluorescence intensity (MFI) values into numbers of antigen molecules expressed per cell (AgE). Lymphoid precursors in the fetal marrow and liver expressed 3-12.5 x 10(3) CD10 molecules/cell with an upper limit of 5 x 10(4)/cell (MaxAgE). The median CD10 AgE in the different cases of acute B-lineage ALL were variable and ranged from undetectable to very high values (> 1.8 x 10(5). In 24 of the 72 cases (33%) tested with QIFI the median CD10 AgE was above the highest values seen in normal samples (> 5 x 10(4)/cell). An additional 23.6% of cases had higher median values than the normal median CD10 AgE. Next, CD10 antigen was quantitated in 78 cases during the routine multiparameter analysis of B-lineage leukemia using CD10/class II/CD34 3-color IF test or CD10/TdT 2-color IF test. The aberrant overexpression was confirmed in 43.6% of ALL cases. The CD10bright display suggested ALL diagnosis even when few cells were available for study, e.g., in early relapse and in ALL masquerading as aplastic anemia. The levels of CD10 expression were maintained in relapse. In addition, different CD10 levels were associated with the various chromosomal alterations: high CD10 levels (> 3 x 10(4)/cell) with hyperdiploidy, low CD10 levels (1.8-4 x 10(3)/cell) with the t(1;19) and undetectable levels (< 1.2 x 10(3)/cell) with the t(4;11) translocations.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers, Tumor↗
PubMed1994

The specific recognition by macrophages of CD8+,CD45RO+ T cells undergoing apoptosis: a mechanism for T cell clearance during resolution of viral infections.

During viral infections, CD8+,CD45RO+ T populations expand. These primed cells express abundant levels of cytoplasmic granules that contain perforin and TIA-1. Recent work has suggested that the majority of this CD8+ population downregulates Bcl-2 protein expression and is destined to undergo apoptosis. In this study we have investigated the elimination of these apoptotic CD8+ T cells by both human monocyte-derived and murine bone marrow macrophages. We have found that these phagocytes recognize and ingest both apoptotic CD8+ and CD4+ T cells using an alpha v beta 3 (vitronectin receptor)/CD36/thrombospondin recognition system, with the same receptors being used in the recognition of apoptotic neutrophils. These data provide new evidence for a mechanism that enables the clearance of greatly increased populations of CD8+ effector cells which are found during viral infections. This enables cellular homeostasis to occur in the host upon resolution of viral diseases in vivo.

Amino Acid Sequence↗
PubMed1994

Use of CD4 lymphocyte count to predict long-term survival free of AIDS after HIV infection.

OBJECTIVE: To estimate the probability of remaining free of AIDS for up to 25 years after infection with HIV by extrapolation of changes in CD4 lymphocyte count. DESIGN: Cohort study of subjects followed from time of HIV seroconversion until 1 January 1993. Creation of model by using extrapolated linear regression slopes of CD4 count to predict development of AIDS after 1993. SETTING: Regional haemophilia centre in teaching hospital. SUBJECTS: 111 men with haemophilia infected with HIV during 1979-85. Median length of follow up 10.1 years, median number of CD4 counts 17. The model was not fitted for three men because only one CD4 measurement was available. MAIN OUTCOME MEASURES: Development of AIDS. INTERVENTIONS: From 1989 prophylaxis against candida and Pneumocystis carinii pneumonia and antiretroviral drugs when CD4 count fell below 200 x 10(6)/l. RESULTS: 44 men developed AIDS up to 1 January 1993. When AIDS was defined as a CD4 count of 50 x 10(6)/l the model predicted that 25% (95% confidence interval 16% to 34%) would survive for 20 years after seroconversion and 18% (11% to 25%) for 25 years. Changing the CD4 count at which AIDS was assumed to occur did not alter the results. Younger patients had a higher chance of 20 year survival than older patients (32% (12% to 52%) for those aged < 15, 26% (14% to 38%) for those aged 15-29, and 15% (0% to 31%) for those aged > or = 30). CONCLUSIONS: These results suggest that even with currently available treatment up to a quarter of patients with HIV infection will survive for 20 years after seroconversion without developing AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Immature CD45RA(low)RO(low) T cells in the human cord blood. I. Antecedents of CD45RA+ unprimed T cells.

A subset of resting T cells expressing low levels CD45RA and CD45RO molecules (< 1 x 10(3)/cell; CD45RA(low)CD45RO(low)) but high levels of CD45RB and CD38 (5 to 25 x 10(3)/cell) were identified in human cord blood. When these CD45RA(low)RO(low) cells were isolated, they failed to survive in culture (< 10% viability at day 3) unless they were co-cultured on fibroblast monolayers. During the co-culture with fibroblasts, these lymphocytes acquired high levels of cytoplasmic and then membrane CD45RA by day 3 without signs of activation. When stimulated with PHA in the absence of fibroblasts the CD45RA(low)RO(low) cells required monocytes or IL-1 to respond; they rapidly perished if neither were present. On optimal mitogenic stimulation for 48 h in the presence of monocytes, > 90% of CD45RA(low)RO(low) T cells showed only transient CD45RA expression and rapidly acquired CD45RO reactivity. After activation for 48 h the stimulated CD45RA(low)RO(low) subset synthesized high levels of IL-2, comparable to mature peripheral T cells. No IL-4 was detected in these stimulated cultures of cord blood T cells. These data taken together suggest that CD45RA(low)RO(low) T cells in the cord blood are the relatively immature antecedents of CD45RA+RO T cells that require stromal factors for survival in a resting state. The same cells need monocytes or IL-1 for their activation to develop after a short CD45RA+ stage into activated CD45RO+RA(low) T cells with potent IL-2 biosynthetic capacity. An additional study of these cells is warranted to confirm that they are in fact the recent emigrants from the thymus, as suggested by similar observations in animal models.

Adult↗
PubMed1994

The progressive differentiation of primed T cells is associated with an increasing susceptibility to apoptosis.

Recent studies have suggested that T cell memory for recall antigens resides in clones of primed T cells with a short inter-mitotic half-life. In humans such cells express an isoform of the leukocyte common antigen termed CD45RO. Nevertheless, little is known of the fate of these primed T cells after initial activation, since no markers are available to distinguish recently primed cells from long-established clones. This report is focused on a spectrum of primed CD4+ T cells characterized by an inverse relationship between the expression of two CD45 epitopes: CD45RB and CD45RO. We show that primed CD4+ T cells progress through many cycles of division from a CD45RBbrightOdull to a CD45RBdullObright state, resulting in a highly skewed distribution of the T cell receptor variable region usage within this particular population. The progressive differentiation defined by the shift from CD45RBbright to CD45RBdull is paralleled by the gradual loss of bcl-2 and gain of Fas expression, two features associated with an increased propensity for apoptosis. At the same time, the highly differentiated CD45RBdull cells selectively lose the capacity to synthesize interleukin (IL)-2, a cytokine which is particularly effective in preventing T cell apoptosis, although they produce high levels of IL-4. The inability to produce adequate levels of IL-2 leads to the apoptosis of primed CD45RBdull cells, when they are stimulated in the absence of exogenous IL-2. These observations show the crucial dependence of highly differentiated T cells on the availability of exogenous IL-2, and suggest both a major constraint for the persistence of T cell memory maintained by continually cycling primed cells, and an important mechanism contributing to the maintenance of T cell homeostasis in vivo.

Apoptosis↗
PubMed1994

Immunological/physiological relationships in asthma: potential regulation by lung macrophages.

There is now a consensus that T-cell-mediated inflammation and eosinophil activation in the bronchial wall contribute to the pathogenesis of asthma. However, the relationship between these immunopathological mechanisms and the observed physiological aberrations remain unclear. Here, Len Poulter and colleagues identify the links between T-cell-mediated inflammation and bronchial hyperresponsiveness, and propose a hypothesis for asthma pathogenesis in which the combination of immunological and physiological abnormalities may result in the promotion of disease. Furthermore, they suggest that an integral factor in the prevention of this process is the regulation of bronchial T-cell reactivity by a population of immunosuppressive macrophages.

Asthma↗
PubMed1994

Lymphocyte activation in HIV-1 infection. II. Functional defects of CD28- T cells.

OBJECTIVES AND DESIGN: The expression of the accessory molecule CD28 was compared in various populations of T and natural killer (NK) cells from HIV-1-negative and HIV-1-positive individuals and correlated with activation using mitogens in vitro. METHODS: Multiparameter flow cytometric analysis using combinations of CD3 CD28 and other markers was performed together with absolute cell counting in peripheral blood. Blast transformation and proliferative responses were also quantitated using the Cytoronabsolute after stimulation with phytohaemagglutinin (PHA) and anti-CD3. CD28- cells were also purified to confirm the observations. RESULTS: In HIV-1-negative individuals > 90% of CD3+ T cells were CD28+ and responded to stimulation, while CD3- CD16+ CD57+ NK-like cells were CD28- and failed to respond. In HIV-1-positive individuals the expression of CD28 was greatly reduced and the proportion of CD3+CD28- T cells expanded. CD8 lymphocytosis was caused entirely by the accumulation of CD28- T cells and many of these expressed activation markers human lymphocyte antigen-DR, CD38 and CD45RO on their membrane and molecules such as TIA-1 and perforin, associated with cytolytic function, in their cytoplasm. The strong positive correlation (r = 0.66) between the lack of CD28 expression and the poor proliferation from HIV-1-positive individuals was confirmed by demonstrating that only CD28+ cells transformed into lymphoblasts and proliferated. Although the CD28- including CD3+ T cells transiently expressed CD25 (interleukin-2R alpha), they did not undergo blastogenesis or activation measured by bromodeoxyuridine uptake and died after 3-4 days in culture. These observations were confirmed in costimulation experiments with anti-CD2 and anti-CD28. CONCLUSION: In HIV-1 infection activated CD3+CD28- T cells accumulate but are unresponsive to mitogens and anti-CD28. These cells appear to represent terminally differentiated effector cells which fail to respond to further stimuli because of the absence of a CD28 second signal.

Adult↗
PubMed1994

HIV seroprevalence in a London same-day testing clinic.

OBJECTIVES: To determine the prevalence of HIV infection among people attending a confidential, non-genitourinary medicine based testing clinic that provides HIV antibody test results on the day of consultation. METHODS: Retrospective analysis of data collected on 2635 individuals attending the Same-Day HIV Testing Clinic at the Royal Free Hospital, London between March 1992 and February 1993. RESULTS: A total of 1612 men and 1023 women were tested for HIV antibody. The primary risk for HIV infection was heterosexual (71.7%; 1889 out of 2635) and homosexual contact (24.5%; 646 out of 2635). Fifty-four individuals were given positive HIV test results (46 men, median age 34 years; eight women, median age 27 years). Overall HIV seroprevalence was 2.0% (95% confidence interval, 1.5-2.5). HIV seroprevalence was highest among homosexual men (6.5%; 41 out of 635) and injecting drug users (5.7%; four out of 70). The rates for heterosexual men and women were 0.2% (two out of 915) and 0.7% (seven out of 974), respectively. Of the 54 individuals who were HIV-antibody-positive, 44 were Centers for Disease Control and Prevention stage II/III, eight stage IV and one was tested at the time of seroconversion (stage I; data were not available for one patient). Of the total numbers attending this clinic 27% (702 out of 2635) had previously been tested and received a negative result. Of a total of 54 HIV-antibody-positive individuals, 40% (21) had previously received a negative test result. CONCLUSIONS: The data suggest that seroprevalence amongst homosexual men attending a designated HIV testing clinic in London is lower than that reported by genitourinary clinic based testing sites. The large number of repeat testers who subsequently became infected with HIV suggests that there is a population requiring specific targetting for HIV risk reduction.

AIDS Serodiagnosis↗
PubMed1994

Beta-2 microglobulin as a predictor of prognosis in HIV-infected men with haemophilia: a proposed strategy for use in clinical care.

Whilst the prognostic value of serum beta-2 microglobulin (s-beta 2m) is well documented, the lack of a simple strategy for its use means that it is rarely ever measured in clinical practice. The prognosis associated with s-beta 2m at two different points in HIV infection, as defined by the CD4 count, was studied in a cohort of 111 men with haemophilia registered at the Royal Free Hospital School of Medicine, London. At CD4 counts of 0.5 and 0.2 x 10(9)/l, a raised s-beta 2m level was significantly associated with an increased risk of developing AIDS (P = 0.002 and 0.022 respectively, adjusted for the patient's age). Kaplan-Meier progression rates to AIDS by 4.5 years after a CD4 count of 0.5 x 10(9)/l were 57% (95% CI 32-82%) in those with s-beta 2m levels of 3 mg/l or more, but 20% (95% CI 4-36%) in those with s-beta 2m levels of less than 3 mg/l. By 3.5 years after a CD4 count of 0.2 x 10(9)/l, Kaplan-Meier progression rates to AIDS were 75% (95% CI 52-98%) in those with s-beta 2m levels of 3.8 mg/l or more, and 47% (95% CI 29-66%) in those with s-beta 2m levels of less than 3.8 mg/l. In the absence of acute viral infections, a raised s-beta 2m indicates those who will tend to progress to AIDS more rapidly than those with lower s-beta 2m levels and the same CD4 count. S-beta 2m levels in general are likely to be higher in haemophilia patients than in other, non-haemophilic risk groups. Whilst care should be taken, therefore, when applying our chosen cut-off values to non-haemophilic patients, our findings support the introduction of prophylaxis and antiviral therapies at a higher CD4 count in those with raised s-beta 2m levels relative to other patients in the same risk group whilst delaying treatment in those with lower CD4 counts, but relatively normal s-beta 2m levels.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Role of bcl-2 and apoptosis in viral infections.

For decades immunobiologists have focussed on lymphocyte activation leading to cellular proliferation as a means by which the numbers of antigen-responsive cells can be increased. The pendulum has now swung back and questions are being raised about the way in which the size of the activated lymphocyte populations, such as those found during certain acute viral infections, can be controlled. The process of apoptosis has gained widespread recognition as a physiological means by which unwanted cells can be removed. In this review we will discuss recent observations on the control of apoptosis in the activated and expanded T cell populations found during viral infections and how this process co-exists with certain mechanisms which enable the retention of the fittest cells which can participate in subsequent encounters with virus.

Animals↗