Pattern of CD4+ T cell loss in HIV infection.
Explore the source record for details and available documents.
CD4-Positive T-Lymphocytes↗
Biomedical subjects
G Janossy
Publications and source records attributed to G Janossy.
Progression of HIV disease in a haemophilic cohort followed for 11 years and the effect of treatment.
OBJECTIVE: To describe the progression of HIV disease in a haemophilic cohort and to show the influence of treatment. DESIGN: 11 year longitudinal clinical and laboratory study. SETTING: A haemophilia centre. PATIENTS: 111 patients infected with HIV during October 1979 to July 1985. MAIN OUTCOME MEASURES: Symptoms of HIV infection, AIDs, and death. INTERVENTIONS: 26 asymptomatic patients started taking zidovudine or placebo (1000 mg/day) during November 1988 to February 1990; 10 patients with CD4+ counts of 0.2 x 10(9)/l started zidovudine 500 mg/day during January to November 1990. 35 patients used pentamidine for primary or secondary prophylaxis. RESULTS: At 11 years from seroconversion the estimated rate of progression to AIDS was 42% (95% confidence interval 27% to 57%); to symptoms 85% (75% to 95%); and to death 41% (25% to 57%). Progression to AIDS was significantly faster in patients aged 25 and over than in those aged less than 25 (relative risk 5.0 (2.4 to 10.4); p less than 0.00001) and in those with previous cytomegalovirus infection than in those not infected (relative risk 3.0 (1.4 to 6.8); p = 0.006). 16 of 27 (59%) patients with p24 antigenaemia developed AIDS compared with 17 of 84 (20%) patients without p24 antigen (p less than 0.001). The risk of progression to AIDS before 30 November 1988 in patients with CD4+ counts less than or equal to 0.2 x 10(9)/l was higher than after November 1988 (relative risk 1.9 (0.85 to 4.43); p = 0.1). For 1989 and 1990 the observed cumulative numbers of AIDS cases (among 81 patients with sufficient CD4+ counts) were 22 and 25 compared with 29 and 37 predicted from the rate of fall of CD4+ counts up to the end of 1988 (p = 0.03). CONCLUSION: Treatment seems to be reducing the progression of HIV disease in this haemophilic cohort.
Acquired Immunodeficiency Syndrome↗
Open access clinic providing HIV-I antibody results on day of testing: the first twelve months.
OBJECTIVES: To determine the sociodemographic profile, risk category, and prevalence of HIV-I infection among people attending a clinic providing counselling, medical advice, and results of HIV-I antibody testing on the day of consultation; to determine the stage of infection and peripheral blood CD4 cell count among attenders with detectable HIV-I antibodies. DESIGN: Analysis of prospectively collected data for the 12 months from March 1989. SETTING: Same day testing clinic run by the HIV/AIDS team at an urban teaching hospital. PATIENTS: 561 consecutive people choosing to attend and proceeding to HIV-I testing. RESULTS: The demand for the service caused it to run to capacity within six months. The median age of those attending was 28 years and 65% (364 patients) were male. The overall prevalence of HIV-I infection was 3.9% (22 patients). The greatest prevalence was in men reporting their primary risk as homosexual contact (11.9%, 13/109). The median CD4 cell count in the 22 patients who had detectable HIV-I antibodies was 0.31 x 10(9) cells/l (normal range 0.5 x 10(9)/l to 1.2 x 10(9)/l). Twenty of these patients were asymptomatic (Centers for Disease Control stages II or III), 14 had CD4 cell counts below 0.5 x 10(9)/l. CONCLUSIONS: There is a recognisable demand for a service providing rapid results of HIV-I antibody testing in this setting. The overall seroprevalence of 3.9% is comparable with the 5.8% reported from freestanding clinics in the United States. Most patients with HIV-I antibodies detected in this way are asymptomatic but could benefit from early medical intervention because of low CD4 cell counts.
Acquired Immunodeficiency Syndrome↗
Stages of T-cell receptor protein expression in T-cell acute lymphoblastic leukemia.
In this study five monoclonal antibodies (MoAbs) to T-cell receptor (TCR) proteins (WT31, alpha F1, beta F1, TCR delta-1 and delta TCS-1) were used to identify discrete maturative stages in 40 cases of T-cell acute lymphoblastic leukemia (T-ALL). These MoAbs reacted exclusively with CD3+ T cells and did not label B-lineage and myeloid cells. In 17 of the 40 T-ALL cases studied the leukemic blasts lacked membrane and cytoplasmic TCR chains (group I). In 12 cases cells did not have membrane CD3/TCR but expressed cytoplasmic TCR proteins heterogenously: nine cases had cytoplasmic TCR beta chains (beta F1+, alpha F1-; group II), one case had cytoplasmic TCR alpha chains (alpha F1+, beta F1-; group III), and two cases were labeled by both alpha F1 and beta F1 MoAbs (group IV). The remaining 11 cases were mCD3+: nine were TCR alpha beta+ (group Va) and two exhibited TCR gamma delta (TCR delta-1+, delta TCS-1+; group Vb). The analysis of the TCR beta, -gamma, and -delta gene configurations in 23 of the 40 T-ALLs showed that: (1) the lack of TCR protein expression was due to the lack of TCR gene rearrangements only in one of nine cases; (2) five of five TCR beta+, TCR alpha- cases studied had germline TCR alpha genes (ie, no detectable TCR delta gene deletions); (3) seven of eight cases with TCR delta gene deletions expressed TCR alpha proteins, whereas in 12 of 20 of the T-ALLs with TCR beta gene rearrangements the synthesis of the corresponding protein occurred; only 2 of 16 cases with rearranged TCR delta genes expressed TCR delta chains. The T-ALL categories identified with anti-TCR MoAbs did not have additional characteristic phenotypic patterns and may correspond to the normal stages of T-cell development more precisely than those defined by other differentiation antigens.
Adult↗
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↗
Human CD4+CD45R0+ and CD4+CD45RA+ T cells synergize in response to alloantigens.
Alloantigens, unlike recall antigens, activate both CD45RA+ (naive) and CD45R0+ (memory) CD4+ cells to the same extent. These T cell subsets may therefore interact with each other in response to alloantigens on transplanted grafts. We have investigated if the ability of activated CD4+CD45RA+ and CD4+CD45R0+ T cells to produce and respond to interleukin 2 (IL2) and IL4 may be involved in this interaction. After activation, both subsets up-regulate their IL2 receptor (IL2R) and IL4R expression, yet IL4 substantially enhanced the proliferation of the CD4+CD45RA+ but not of the CD4+CD45R0+ T cell subset, while IL2 increased the proliferation of CD4+CD45R0+ but not of the CD4+CD45RA+ T cells. Significantly, the CD4+CD45RA+ T cells synthesized two- to threefold more mRNA for IL2 than the CD4+CD45R0+ subset, while the CD4+CD45R0+ T cells synthesized mRNA for IL4 and interferon-gamma exclusively. The addition of IL2 to alloactivated CD4+CD45R0+ T cells further up-regulated their production of all three lymphokine mRNA; in contrast, IL4 induced an increase in mRNA for IL2 in only the alloactivated CD4+CD45RA+ subset. The reciprocity in the ability of both these CD4+ T cells to synthesize and respond to IL2 and IL4 may provide a rationale for the regulation of lymphokine interactions in vivo. Furthermore, the synergy between these subsets in response to alloantigens, which was directly quantitated by co-culturing CD4+CD45RA+ and CD4+CD45R0+ cells together prior to activation, may potentiate the alloreactivity against transplanted grafts in vivo.
Antigens, CD↗
The synergy between naive and memory T cells during activation.
Naive and memory T-cell subsets differ in their ability to synthesize and respond to a variety of cytokines in vitro and each subset can produce cytokines that amplify the response of the other subset. The significance of these interactions to antigen responsiveness has, until now, been unclear. In this article Arne Akbar and colleagues point out that both subsets are activated to the same extent by alloantigen and suggest that synergy may be an important event in initiating potent responses against transplanted allografts.
Animals↗
Immune parameters in HIV infection--a practical guide.
As it has become clear that HIV causes a progressive breakdown in immune competence that can be precisely measured, the introduction of diagnostic tests in placebo-controlled clinical trials has taken on a new importance. The task for clinical immunologists, namely to standardize these techniques through international collaboration using current understanding of pathogenesis, was the subject of a recent workshop.
CD4-CD8 Ratio↗
p24 antigenaemia, CD4 lymphocyte counts and the development of AIDS.
A cohort of 111 HIV-infected haemophiliacs has been followed for up to 11 years, during which time 33 patients have been diagnosed with AIDS. Twenty-seven of the cohort developed detectable p24 antigenaemia while remaining free of AIDS. These patients experienced an increased risk of progression to AIDS compared with those patients who were persistently p24-negative (relative risk 7.24; P less than 0.0001, Cox proportional hazards model). The relative risk was reduced to 5.42 (P less than 0.0001) after adjustment for age and cytomegalovirus seropositivity. After adjustment for the patients' declining CD4 lymphocyte count during follow-up, the relative risk fell dramatically to 1.97 and became non-significant (P = 0.2). p24-antigenaemic patients tended to develop AIDS at levels of similar CD4 lymphocyte counts to those who were persistently p24-antigen-negative (median CD4 lymphocyte counts, 70 and 50 x 10(6)/l, respectively). These results suggests that the association between p24 antigenaemia and the rate of progression to AIDS can be explained largely by a more rapid decline in CD4 lymphocyte count among patients with p24 antigenaemia than in those without. The major pathological effects of increased plasma viral load, as detected by the presence or absence of p24 antigenaemia, appear to act via progressive CD4 lymphocyte depletion.
Acquired Immunodeficiency Syndrome↗
The effect of a chimeric mouse-human CD7 antibody on human T, natural killer, and lymphokine-activated killer cell activity in vitro.
A chimeric CD7 antibody has been constructed with mouse variable and human constant regions and is currently being assessed in the prophylaxis of renal graft rejection. In this study we have investigated if this antibody or its murine parental form inhibits the function of a number of immune effector mechanisms involved in host defense against infection and/or malignancy. Most memory T cells and all natural killer cells express the CD7 antigen and could therefore be affected by CD7 antibody. Murine and chimeric CD7 antibodies significantly inhibit the alloproliferation of naive (65 +/- 4% and 66 +/- 8%, respectively) but not memory T cells (86 +/- 2% and 98 +/- 4%, respectively) in a primary mixed lymphocyte reaction relative to the negative control CD10 antibody (P less than 0.001). The memory T cell proliferative response to recall antigen is also largely unaffected by murine and chimeric CD7 antibodies relative to the negative control antibody (91 +/- 12% and 103 +/- 10%, respectively). The CD7 antigen is almost completely modulated from the surface of NK cells after incubation for 24 hr with either the murine or chimeric CD7, but not the CD10, negative control. The modulation of CD7 antigen by antibody, however, does not affect the cytotoxic function of either the NK or lymphokine-activated killer cells significantly. Preincubation with the chimeric antibody however, consistently showed a small inhibition relative to the negative control of 75-80% in NK assays and to 80-90% in LAK assays. These data suggest that both murine and chimeric CD7 antibodies may have a selective effect on alloproliferation but may largely spare a major component of the host's innate immunity as well as memory T cell proliferation to previously encountered antigens.
Antibodies↗
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↗
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↗
Molecular investigation of 19p13 in standard and variant translocations: the E12 probe recognizes the 19p13 breakpoint in cases with t(1;19) and acute leukemia other than pre-B immunophenotype.
The gene E2A has recently been cloned, mapped to 19p13 and shown to be rearranged in cases of pre-B acute lymphoblastic leukemia (ALL) with t(1;19) (q23;p13). Nine cases with a 19p13 breakpoint, four having a phenotype other than pre-B, have been investigated with the E12 probe to the E2A gene. Five cases had t(1;19) (q23;p13) and C-ALL with pre-B phenotype in four out of four cases tested. Two cases had t(1;19) (q21;p13), one with Null cell phenotype, t(4;11), and 'jumping translocations' and the other with acute non-lymphocytic leukemia M5 following bone marrow transplantation for C-ALL. Variant translocations in patients with ALL were t(15;19) (q15;p13) and t(17;19) (q21;p13). Southern blotting with E12 showed rearrangement in the cases with t(1;19) (q23;p13) and t(1;19) (q21;p13), but not in other cases with variant 19p13 breakpoints. Thus rearrangement of the E2A gene is not restricted to cases with pre-B ALL but may also occur in acute leukemias with other immunological phenotypes. Failure to detect rearrangement in 19p13 variants may be due to an E2A breakpoint outside the E12 recognition region. Alternatively, there may be further genes in this location with relevance to leukemogenesis.
Adolescent↗
Prevention of graft-versus-host disease with T cell depletion or cyclosporin and methotrexate. A randomized trial in adult leukemic marrow recipients.
In adult leukemic marrow recipients of HLA identical sibling marrow, 23 patients were randomized to T cell depletion and 25 received cyclosporin (CSA) and four doses of methotrexate (MTX) to prevent graft-versus-host disease (GVHD). Anti-CD8 and anti-CD6 antibodies plus complement depleted 95.3 +/- 5.8% (mean +/- SE) CD3 cells. All patients engrafted except one who died early. Patients receiving T cell-depleted marrow had a faster time to 0.2 x 10(9) WBC/l (p less than 0.001), but required more erythrocyte units (p = 0.03). Platelet transfusions, infections and time in hospital did not differ. The incidence of grade II-III acute GVHD was 23% following T cell depletion and 12% for those receiving CSA + MTX. Chronic GVHD occurred in 51% and 23% in the two groups, respectively (p = 0.06). Recipients of T cell-depleted marrow who developed grade I-III acute GVHD received more T cells compared to those without acute GVHD (p = 0.02). The major cause of death in both groups was relapse, the cumulative incidence of which, at 4 years, was 39% in the recipients of T cell-depleted marrow and 54% in the CSA + MTX group. The 3-year actuarial leukemia-free survival was 42% and 44% in the two respective groups.
Adult↗
Phenotypic features and proliferative activity of B cell progenitors in X-linked agammaglobulinemia.
In this study, we applied mAb and heterologous antisera in double marker combinations to investigate the phenotype and the proliferative activity of immature B lineage cells in XLA. Bone marrow (BM) samples from eight male adult patients with no circulating B lymphocytes were studied. The proportions and the phenotype of the earliest identifiable B cell progenitors, expressing nuclear terminal deoxynucleotidyl transferase (TdT), cytoplasmic CD22, and membrane CD19 and CD10 were identical to those observed in normal BM. In XLA these cells represented 1.2% to 22% of BM mononuclear cells; 5% to 42% and 1% to 45% of such cells weakly expressed CD20 and CD37, respectively, and invariably lacked CD13 and CD33. Cytoplasmic mu+ sIg- pre-B cells were seen in low numbers (0.1% to 0.3%) in four samples and were undetectable in the remaining four. Consequently, the ratio TdT+/c mu+ was greater than 100 in five out of eight samples studied in contrast to the less than 10 values seen in normal individuals. The proliferative activity of B lineage progenitor cells was studied by using Ki67 and anti-bromodeoxyuridine mAb. Although the proliferation of TdT+ cells in XLA was comparable with that seen in normal BM samples (24% to 59% of TdT+ were Ki67+ and 11% to 27% incorporated bromodeoxyuridine), this was dramatically reduced in the c mu+ cells (no c mu+, Ki67+ seen in three samples where pre-B cells were observed). Thus, the abnormalities of B cell differentiation in XLA are first seen at the c mu+ pre-B stage and suggest a maturation block in the transition between TdT+, c mu- pre-pre-B cells and c mu+ pre-B cells. The severity of this block may be variable, allowing the generation of a near normal number of pre-B cells in some patients, which nevertheless have a defective proliferative activity. Finally, our study further supports the concept that the effects of the "XLA gene" are confined within the B lineage by demonstrating that the proportions of T cells bearing TCR-alpha beta and TCR-gamma delta in XLA are similar to those seen in normal individuals.
Agammaglobulinemia↗
The immunologic detection of minimal residual disease in acute leukemia.
Certain combinations of differentiation antigens are expressed on leukemia blasts and are absent or extremely rare among normal progenitors in the fetal liver and fetal and regenerating bone marrow. These combinations include cCD3/TdT, a thymic feature retained on thymic-acute lymphoblastic leukemia (T-ALL) blasts outside the thymus, and the coexpression of TdT and myeloid markers (CD13, CD33) on a proportion of ALL and acute myeloid leukemia (AML). Thus, double marker immunofluorescence assays are operationally leukemia-specific and can be applied in 35% of acute leukemias for detecting minimal disease at a less than 10(-4) level; only rare cases, 2 of 35 in our study, switch these relevant features during relapse. The sensitivity and specificity of these assays was tested as follows. First, bone marrow samples taken from patients who had originally presented with blasts expressing the leukemia-associated combinations but were in full morphologic remission were studied, and varying numbers (less than 0.01% to 10% of the mononuclear fraction) of cells with aberrant features were identified in 11.6% of the cases. Second, the outcome of 19 patients with minimal disease identified immunologically while in complete morphologic remission was investigated: all 19 patients have developed systemic relapse within 4 to 25 (median 14.5) weeks. In contrast, 17 of 25 patients also morphologically in complete remission and without residual disease identifiable immunologically after repeated testing are still in morphologic and immunologic remission (follow-up 17 to 114 weeks, median 28 weeks). Only eight patients in this group have relapsed so far: in two patients the relapse was localized in the cerebrospinal fluid, while in six patients a systemic relapse was observed 6 to 51 (median 21.5) weeks after the last negative immunologic bone marrow examination. In conclusion, no false-positive results were detected with these sensitive assays, and the introduction of appropriately planned prospective studies, including the immunologic detection of residual leukemia, is justified on the basis of these observations.
Antigens, CD↗
Immunophenotyping in haematological diagnosis.
Explore the source record for details and available documents.
Acute Disease↗
Inhibition of alloresponsive naive and memory T cells by CD7 and CD25 antibodies and by cyclosporine.
Human naive and memory T cells can be isolated from each other by their CD45RA and CD45RO expression, respectively. This enables the assessment of their differential sensitivities to immunosuppressive agents for the first time. We have investigated the ability of cyclosporine or CD7 and CD25 antibodies to selectively block alloantigen stimulated naive and memory T cells in vitro. CD7 antibodies blocked the proliferation of naive (P less than 0.025) but not memory T cells in a primary MLR. CD25 antibody inhibited both naive and memory subsets but a significantly greater effect was found on the memory T cells (P less than 0.005). The constitutive CD7 and CD25 antigen expression on resting naive or memory T cells was related to the inhibitory activities of these antibodies on both subsets. Accordingly, naive T cells expressed more CD7 antigen than memory cells while memory T cells displayed low levels of CD25 antigen that was absent from naive populations before activation. Cyclosporine, like CD25 antibody, inhibited both subsets in a primary MLR but had a greater effect on memory cells (P less than 0.02). Memory T cells, therefore, are more dependent than naive cells on IL-2 for proliferation. There was great individual variation in the ability of CsA to block the MLR. The simultaneous addition of CD25 or CD7 antibody together with CsA, however, enhanced the MLR inhibition as the effects of all three were additive. This suggested interference by these agents at different points during T cell activation. Thus, in CsA sensitive individuals, one-tenth of the optimal CsA concentration together with CD25 antibody maintained maximum immunosuppression in vitro. These results demonstrate the possibility of using CD7 and CD25 antibodies for selective inhibition of naive or memory T cells and also the possibility of augmenting the inhibition of and reducing the CsA concentration required for clinically effective immunosuppression.
Antibodies, Monoclonal↗