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Biomedical subjects

M Bofill

Publications and source records attributed to M Bofill.

At least 55 records · Page 3Linked to original sources
PubMed1994

Flow cytometric analysis of the stimulatory response of T cell subsets from normal and HIV-1+ individuals to various mitogenic stimuli in vitro.

A novel technique is described which allows the study of the responses of T cell subpopulations stimulated in bulk cultures without interfering with cell-cell interactions. The number and phenotype of lymphoblasts developing following stimulation with phytohaemagglutinin (PHA), anti-CD3, staphylococcal protein A (SPA) and pokeweed mitogen (PWM) was determined in HIV-1- and HIV-1+ patients using a new five-parameter flow cytometric method. We found that normal T cells responded faster to PHA than to any of the other mitogens tested. The peak of the PHA response occurred on day 3, followed by anti-CD3 and SPA on day 4 and PWM mitogen on day 5. Although PHA and anti-CD3 stimulated up to 95% and 80% of lymphocytes, respectively, SPA and PWM stimulated only 40% and 30% of cells, respectively. A defective T cell response was observed in lymphocytes cultured from asymptomatic HIV-1+ patients compared with negative controls. This loss of response was related to a selective mortality of T cells following mitogenic stimulation, referred to as activation-associated lymphocyte death (AALD). The results showed that stronger mitogens (PHA and anti-CD3) induced AALD in a larger proportion (50-60%) of T cells than weaker mitogens such as SPA and PWM (30-40%), and that AALD affected different lymphocyte subsets to different extents. AALD occurred more frequently in total CD8+ and CD45RO+ T cells compared with CD4+ and CD45RA+ T cells, but memory CD4+ T cells were the population most severely affected in samples from HIV-1+ donors.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Acquired immunodeficiency syndrome (AIDS) risk in recent and long-standing human immunodeficiency virus type 1 (HIV-1)-infected patients with similar CD4 lymphocyte counts.

The loss of CD4 lymphocytes is known to be an important component of human immunodeficiency virus type 1 (HIV-1) pathogenesis. It remains unclear, however, whether the importance of the CD4 lymphocyte count is such that individuals who have been infected for widely different lengths of time, but for whom the CD4 lymphocyte count is the same, have the same risk of developing acquired immunodeficiency syndrome (AIDS). The authors directly addressed this question for 111 HIV-1-infected hemophiliacs who had been followed for up to 12 years from seroconversion and for whom a median of 16 CD4 lymphocyte counts had been made. Thirty-eight patients had developed AIDS by January 1, 1992. As of August 1, 1985, the time from seroconversion to AIDS ranged from 3 weeks to almost 6 years. The risk of AIDS increased with time from seroconversion (relative hazard = 1.25 per year; p = 0.09). CD4 lymphocyte count was strongly related to time from seroconversion and also to the risk of AIDS (relative hazard = 3.25 per 100/mm3; p < 0.00005). In a bivariate Cox regression model, the relative hazard for time from seroconversion fell markedly towards unity (1.05; p = 0.7), while that for CD4 lymphocyte count remained unchanged. This suggests that time from seroconversion is a relevant factor in HIV-1 infection only insofar as it provides information as to the probable degree of loss of CD4 lymphocytes. If the number of these cells is known, time from seroconversion seems to be of little additional value in assessing the risk of AIDS. This finding has implications for the clinical assessment of individual patient prognosis, for the design of epidemiologic studies of HIV-1 infection, and for our understanding of how HIV-1 causes disease.

Acquired Immunodeficiency Syndrome↗
PubMed1993

The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory.

The bcl-2 gene product has been shown to prevent apoptotic cell death. We have now investigated the bcl-2 protein expression by resting and activated mature T cell populations. Freshly isolated CD45RO+ T cells within CD4+ and CD8+ subsets expressed significantly less bcl-2 than CD45RO- (CD45RA+) T cells (p < 0.001). When CD45RA+ T cells within both CD4+ and CD8+ subsets were activated in vitro, the transition to CD45RO phenotype was associated with a decrease in bcl-2 expression. Patients with acute viral infections such as infectious mononucleosis caused by Epstein-Barr virus infections or chickenpox, resulting from varicella zoster virus infection, had circulating populations of activated CD45RO+ T cells which also showed low bcl-2 expression. In these patients, a significant correlation was seen between low bcl-2 expression by activated T cells and their apoptosis in culture (r = 0.94, p < 0.001). These results suggest that the primary activation of T cells leads to the expansion of a population that is destined to perish unless rescued by some extrinsic event. Thus the suicide of CD45RO+ T cells could be prevented by the addition of interleukin 2 to the culture medium which resulted in a concomitant increase in the bcl-2 expression of these cells. Alternatively, apoptosis was also prevented by coculturing the activated T lymphocytes with fibroblasts, which maintained the viability of lymphoid cells in a restinglike state but with low bcl-2 expression. The paradox that the CD45RO+ population contains the primed/memory T cell pool yet expresses low bcl-2 and is susceptible to apoptosis can be reconciled by the observations that maintenance of T cell memory may be dependent on the continuous restimulation of T cells, which increases their bcl-2 expression. Furthermore, the propensity of CD45RO+ T cells to extravasate may facilitate encounter with fibroblast-like cells in tissue stroma and thus be an important additional factor which promotes the survival of selected primed/memory T cells in vivo.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Lymphocyte activation in HIV-1 infection. I. Predominant proliferative defects among CD45R0+ cells of the CD4 and CD8 lineages.

OBJECTIVES AND DESIGN: The proliferative defects of CD4 and CD8 cells taken from 474 HIV-1-seropositive individuals during various stages of disease were quantitated. Phytohaemagglutinin (PHA) and soluble anti-CD3 were used in optimal mitogenic concentrations in the presence of recombinant interleukin-2 (rIL-2) and conditioned medium, and the proliferation of cells from HIV-1-seropositive donors was assessed in co-culture with HIV-1-seronegative cells in order to exclude effects of cytokine deficiency. Defects within the CD45RA+ ('unprimed') and CD45R0+ ('primed') T-cell populations were also investigated. METHODS: Quantitative immunofluorescence and double and triple labelling in flow cytometry were performed for (1) CD25 (IL-2 receptor alpha chain) expression, (2) lymphocyte and T-cell survival, and (3) blast transformation and proliferation--in relation to the original input of cells for each subpopulation. RESULTS: T cells from normal and HIV-1-seropositive donors were CD25+ at day 1. In HIV-1-seropositive patients a variable number of CD4 and CD8 lymphocytes failed to further increase CD25, and died as a sign of activation-associated lymphocyte death (AALD). Forty-two per cent of asymptomatic subjects, including 32% of those with CD4 cell counts > 400 x 10(6)/l, showed a poor blast transformation (< 30% blasts). Cells from HIV-1-seropositive donors showed poor blast responses when co-cultured with HIV-1-seronegative cells; both CD4 and CD8 cells were handicapped. In asymptomatic HIV-1-seropositive people T cells with the CD45R0+ RA- ('primed') phenotype were three to five times more vulnerable to AALD than the CD45RA+ RO- ('unprimed') cells. In patients in Centers for Disease Control and Prevention (CDC) disease stage IV both CD45R0+ and -RA+ populations were severely affected. CONCLUSIONS: This is the first quantitative analysis to demonstrate that in HIV-1 infection mitogen-stimulated CD45R0+ ('primed') T cells preferentially die upon activation. Both the CD4 and CD8 lineages are affected, as seen in animal models of graft versus host disease. AALD may explain defects of immunological memory. The analysis of AALD may be a suitable assay for studying whether antiviral drugs influence the proliferative responses of lymphocytes.

CD3 Complex↗
PubMed1993

CD8 lymphocyte counts and serum immunoglobulin A levels early in HIV infection as predictors of CD4 lymphocyte depletion during 8 years of follow-up.

OBJECTIVE: To assess the ability of the CD8 lymphocyte count and immunoglobulin (Ig) A level, measured at the early stage of HIV infection when the CD4 lymphocyte count remains relatively high, to predict the future rate of CD4 lymphocyte loss and hence the risk of AIDS. DESIGN: Cohort of recently infected haemophiliacs with relatively high CD4 lymphocyte counts followed for up to 8.5 years from baseline measurement of CD8 lymphocyte counts and IgA levels. SETTING: A regional haemophilia centre based in a major teaching hospital. PATIENTS: Eighty-four of 111 patients with haemophilia who seroconverted to HIV between 1979 and 1985 in whom CD8 lymphocyte counts and IgA levels were measured soon after seroconversion (mean, 2.7 years; maximum, 5 years) while CD4 lymphocyte counts remained relatively high (median, 600 x 10(6)/l; minimum, 300 x 10(6)/l). OUTCOME MEASURES: Development of severe immunodeficiency defined by a CD4 lymphocyte count falling below 50 x 10(6)/l, and AIDS. RESULTS: Individuals with high CD8 counts (P < 0.008) and high IgA levels (P < 0.003) at baseline experienced a more rapid rate of CD4 lymphocyte loss than those with low baseline levels. A score was derived to combine the predictive ability of CD8 count and IgA level. Estimated proportions with CD4 counts below 50 x 10(6)/l after 8 years of follow-up were 100, 30 and 14% for those with high, intermediate and low baseline scores, respectively. The CD8/IgA score showed similar ability to predict the future occurrence of AIDS (P < 0.0001; log-rank test). CONCLUSION: Immune activation seen in HIV infection, as reflected by raised CD8 counts and IgA levels, appears to be linked to the process of CD4 lymphocyte depletion. Measurement of these markers in the years following infection, when CD4 lymphocyte counts remain high, provides a first indication of a patient's long-term prognosis.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Immunodeficiency and the risk of death in HIV infection.

OBJECTIVE: To describe the rate of development of immunodeficiency in human immunodeficiency virus (HIV) infection and to relate this to the risk of death. DESIGN: Inception cohort followed up for up to 12 years from HIV seroconversion until January 1, 1992. SETTING: A regional hemophilia center based in a major teaching hospital. PATIENTS: All 111 patients with hemophilia who seroconverted to HIV-1 between 1979 and 1985 were registered at the center. Patients have been closely followed up clinically and immunologically. OUTCOME MEASURES: Development of immunodeficiency, defined by a CD4 lymphocyte count falling beneath 0.20 and 0.05 x 10(9)/L, and death. RESULTS: Kaplan-Meier estimates suggest that almost half (46%; 95% confidence interval [CI], 26% to 66%) of patients alive 12 years after seroconversion will have a CD4 lymphocyte count that has remained above 0.05 x 10(9)/L. Thirty-five percent (95% CI, 22% to 48%) remain above 0.20 x 10(9)/L. Thirty-seven patients died of HIV-related causes, and there was a 52% probability (95% CI, 35% to 69%) of HIV-related mortality by 12 years from seroconversion. Mortality risk was closely associated with severe immunodeficiency. There was only a 15% chance (95% CI, 6% to 25%) of HIV-related death occurring before a CD4 count of below 0.05 x 10(9)/L had been reached. There was an average of one HIV-related death per 96.7 patient-years of observation before the CD4 count had fallen below 0.05 x 10(9)/L, as compared with one death per 2.5 patient-years of observation after the CD4 count had fallen below this level (P < .0001). CONCLUSIONS: In patients with HIV infection who are closely followed up, the risk of death is low before the CD4 lymphocyte count has fallen to 0.05 x 10(9)/L, a count many patients remain above up to 12 years after seroconversion.

CD4-Positive T-Lymphocytes↗
PubMed1992

Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis.

With the advent of standard flow cytometric methods using two-colour fluorescence on samples of whole blood, it is possible to establish the ranges of CD3, CD4 and CD8 T lymphocyte subsets in the routine laboratory, and also to assist the definition of HIV-1-related deviations from these normal values. In 676 HIV-1-seronegative individuals the lymphocyte subset percentages and absolute counts were determined. The samples taken mostly in the morning. The groups included heterosexual controls, people with various clotting disorders but without lymphocyte abnormalities as well as seronegative homosexual men as the appropriate controls for the HIV-1-infected groups. The stability of CD4% and CD8% values was demonstrated throughout life, and in children CD4 values less than 25% could be regarded as abnormal. The absolute counts of all T cell subsets decreased from birth until the age of 10 years. In adolescents and adults the absolute numbers (mean +/- s.d.) of lymphocytes, CD3, CD4 and CD8 cells were 1.90 +/- 0.55, 1.45 +/- 0.46, 0.83 +/- 0.29 and 0.56 +/- 0.23 x 10(9)/l, respectively. In patients with haemophilia A and B the mean values did not differ significantly. In homosexual men higher CD8 levels were seen compared with heterosexual men and 27% had an inverted CD4/CD8 ratio but mostly without CD4 lymphopenia (CD4 less than 0.4 x 10(9)/l). However, some healthy uninfected people were 'physiologically' lymphopenic without having inverted CD4/CD8 ratios. When the variations 'within persons' were studied longitudinally over a 5-year period, the absolute CD4 counts tended to be fixed at different levels. As a marked contrast, over 60% of asymptomatic HIV-1+ patients exhibited low CD4 counts less than 0.4 x 10(9)/l together with inverted CD4/CD8 ratios. Such combined changes among the heterosexual and HIV-1-seronegative homosexual groups were as rare as 1.4% and 3%, respectively. For this reason, when the lymphocyte tests show less than 0.4 x 10(9)/l CD4 count and a CD4/CD8 ratio of less than unity, the individuals need to be investigated further for chronicity of this disorder, the signs of viral infections such as HIV-1 and other causes of immunodeficiency.

Adolescent↗
PubMed1991

Serial CD4 lymphocyte counts and development of AIDS.

Low CD4 lymphocyte counts are associated with increased risk of progression to AIDS in human immunodeficiency virus (HIV) infection. We investigated the extent to which the timing of progression to AIDS can be explained solely in terms of decline of the CD4 lymphocyte count in 111 haemophiliacs followed for up to 11 years since infection with HIV. A median of 10 CD4 lymphocyte counts were made per patient. By applying a simple linear model for the decline in CD4 lymphocyte counts over time, we estimated the date of development of AIDS in 96 patients who had at least 5 determinations. 84% (81 of 96) of patients were correctly classified as to development of AIDS before Jan 1, 1990 (p less than 0.0001), with this model. The results suggest that differences in the time at which patients with HIV will progress to AIDS can largely be explained by differences in rates of decline of CD4 lymphocyte counts.

Acquired Immunodeficiency Syndrome↗
PubMed1991

More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts.

The tendency for older people with HIV infection to progress more rapidly to AIDS than younger people was studied in a group of 111 anti-HIV-positive haemophiliacs followed for up to 10 years from seroconversion. After 7 years of seropositivity, those aged over 30 years at the time of the first positive anti-HIV test had a cumulative progression rate to AIDS of 50%, compared with only 12% for those aged 10-19 years (Kaplan-Meier estimates). Overall, the relative risk of developing AIDS by any given time after seroconversion was 1.45 for each 10 year increase in age (p = 0.002; 95% confidence limits of 1.15, 1.85; Cox proportional hazards model). After adjustment for the CD4+ T-cell count (median of 10 count measurements per patient, fitted as a time-dependent covariate), the relative risk fell to 1.31 but remained statistically significant (p less than 0.05; 95% confidence limits of 1.03, 1.67). This implies that older people may be at higher risk of progression than their younger counterparts, even if their CD4+ T-cell counts are the same. Hence, prophylaxis against opportunistic infections may be indicated at higher CD4+ T-cell counts in older people than in younger people.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Human B-lymphoid differentiation: normal versus malignant.

In this review the features of B-cell development and differentiation are described for the bone marrow and peripheral B-cell system, in particular that in lymph nodes follicles. These features show many similarities to those of malignant B-cell populations. Frequently the "normal counterparts" of malignant B lineage cells are seen in particularly high frequency in the foetal lymphoid tissues. For example, foetal bone marrow shows abundant CD10+ precursors and foetal lymph nodes contain many CD5+ B cells. These similarities contribute to a better understanding of B-cell malignancy. On the other hand they provide observations also useful in interpretation of immunodeficiency such as X-linked agammaglobulinaemia and lymph nodes after HIV-1 infection. The identification of target cells in lymphoid malignancies will be important for understanding the mechanism of tumour development because the gene alterations also show target cell specificity.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Prediction of progression to AIDS by analysis of CD4 lymphocyte counts in a haemophilic cohort.

Serial CD4 lymphocyte counts were recorded in 112 anti-HIV-positive haemophiliacs who were followed for up to 8 years after seroconversion. The patients remained at low risk of developing AIDS until their CD4 lymphocyte count fell to 0.25 X 10(9)/l. From this point, the risk increased as their count approached zero. Using this result and on the assumption (which is evaluated) that the underlying trend over time in CD4 lymphocyte counts is linear, the predicted rate of progression to AIDS was calculated for the cohort. It was estimated that 73% (95% confidence limits 60-86%) of the cohort will develop AIDS within 15 years of HIV-seropositivity. During 8 years of follow-up, this cohort had shown similar rates of progression to AIDS to other cohorts--haemophilic and otherwise--suggesting that this estimate may well have general applicability. The method described could be used to plan the provision of health-care resources for groups of anti-HIV-positive patients as it allows the number of new cases of AIDS to be predicted year by year, even when the patients' dates of seroconversion are unknown.

Acquired Immunodeficiency Syndrome↗
PubMed1989

The natural history of human immunodeficiency virus infection in a haemophilic cohort.

112 haemophilic patients infected with HIV were followed up with clinical and laboratory assessment between 1 December 1979 and 30 November 1988. Sixty-six (59%) of the patients developed HIV-related clinical symptoms and 22 (20%) developed AIDS. Twenty (18%) of the patients developed p24 antigenaemia. Amongst the 59 patients whose date of seroconversion could be estimated the calculated 8-year cumulative incidence of AIDS was 40% (symptoms 73%). For the whole cohort of 112 patients, the median slope of linear regression of the absolute T4 lymphocyte count was steeper for those with AIDS (-0.113 x 10(9)/l per year) than for those without AIDS (-0.054 x 10(9)/l per year) (P less than 0.02). While 15 cases of AIDS developed during 58 patient-years of follow up after falling below a T4 lymphocyte count of 0.2 x 10(9)/l, only two cases occurred during 450 patient-years before reaching this count. Thus the decline of the T4 lymphocyte count to 0.2 x 10(9)/l may be an appropriate additional end-point for the assessment of new treatments for asymptomatic patients infected with HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1989

The tissue distribution of T lymphocytes expressing different CD45 polypeptides.

The distribution of T lymphocytes expressing the different polypeptides of the leucocyte common antigen (LCA) family detected by CD45R and UCHL1 antibodies has been studied in normal lymphoid tissues. In the thymus most cortical thymocytes express UCHL1 and co-express CD4 and CD8. The more mature membrane CD3+ (mainly medullary) T cells are heterogenous and may express both UCHL1 and CD45R weakly or be restricted to display CD45R or UCHL1 alone. In the medulla both the CD45R+ and UCHL1+ subpopulations contain single positive CD4 and CD8 cells. In tonsils, germinal centre T cells are almost exclusively UCHL1+, CD4+ and a proportion also express HNK-1 (Leu 7) antigen. In the paracortical areas approximately equal numbers of CD45R+ and UCHL1+ cells are found but these separately occupy nests of cells containing one or the other type. Again, both CD45R+ and UCHL1+ cells include single CD4+ and CD8+ lymphocytes. A small proportion (less than 5%) of strongly CD45R+, UCHL1+ double-stained cells are also seen, and these probably represent recently activated lymphocytes. In the gut, small clusters of such strongly double-labelled cells are in the submuscular mucosae while cells of the lamina propria are almost exclusively UCHL1+. Many intra-epithelial lymphocytes are only weakly positive or negative for UCHL1 and appear to be CD45R-. These results are consistent with the view that expression of different CD45 polypeptides identifies successive stages of thymocyte-T-cell maturation and that following their thymic education, unprimed T lymphocytes are CD45R+, while primed memory T cells are UCHL1+. These populations occupy different microenvironments.

Antigens, Differentiation↗
PubMed1987

What kind of morphologically recognizable haemopoietic cells do we inject when doing foetal liver infusion in man?

There is no agreement, how to define the age of the embryo/foetus. From the 15th (fertilization) week onwards the whole foetal liver contains some 10(9) free haemopoietic cells. Before, and up to the 30th-34th weeks, the liver is the main site of haemopoiesis. The differential of embryonic smears (up to wk 9) differs from that of foetal ones. The first invasion of circulating primitive erythroblasts seeding in the liver (early 5th wk) is accompanied by the appearance of a lot of sinusoidal macrophages. Definitive erythropoiesis expands during the 6th-7th wks. Granulocytic representation peaks at 15-16 wks. Megakaryocytes are small and have few nuclei/nuclear lobes. Five to 8, or even more per cent of single haemopoietic cells were lymphoid-like cells in the 5th-6th wk liver smear. These cells precede the development of any lymphoid structure in the foetus. Ordinary lymphocytes amount to less than 2% between 10 and 18 wks, and reached 3% at wk 24. Percentage of dyserythropoietic nuclei in smears has been used to decide whether the injected cells could be regarded as 'physiological' cells. Ten out of 11 apparently healthy foetuses, delivered by hysterectomy/hysterotomy for maternal interest, aged 10 1/2 to 20 1/2 weeks, had mean 4.5% liver dyserythropoiesis. Extremely high dyserythropoiesis was associated with multilineage, instead of overwhelmingly erythroid haemopoiesis.

Cell Differentiation↗
PubMed1986

Separate ontogeny of two macrophage-like accessory cell populations in the human fetus.

Human macrophage-like accessory cells were analyzed as they emerge in the absence of extrinsic antigens during fetal development. Monoclonal antibodies to monocytes/macrophages were used in combination with antibodies to HLA class II molecules. In the yolk sac and mesenchyme sampled at wk 4 to 6 of fertilization age, cells with dendritic morphology formed two populations distinguishable by phenotypic criteria: type i (majority) carried both macrophage-associated (RFD7+) and monocyte-associated markers (UCHM1+) but no detectable HLA-DR antigen, and type ii (minority) constitutively expressed class II (HLA-DR and -DP) but no RFD7 and UCHM1. The emergence of this heterogeneity preceded the formation of both thymus and bone marrow. During additional development, type i and type ii cells seeded to different microenvironments and underwent some additional phenotypic changes. Cells of type i, the RFD7+ population with high lysosomal (acid phosphatase) activity, were seen in the thymic cortex, marginal zone of lymph nodes, splenic red pulp, and in the midst of erythropoietic activity within the bone marrow. These cells were UCHM1- and class II-. Cells of type ii formed the population of HLA-DR+, RFD7- interdigitating cells, early inhabitants of T cell areas in the developing thymic medulla, lymph nodes, spleen, and tonsil. The Type ii cells that had already settled in their nichès expressed not only HLA-DR and -DP but also HLA-DQ, and another class II antigen identified by the antibody RFD1, which shows the restricted tissue distribution of HLA-DQ, but is governed by genes that are outside of and telomeric to the HLA-DQ region (or HLA-DR). Finally, subpopulations of macrophages (RFD7+, acid phosphatase-positive) in the fetal gastrointestinal and hepatic systems were HLA-DR+; the latter appear to include precursors of Kupffer cells in the developing liver.

Acid Phosphatase↗