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Biomedical subjects

S Plaeger-Marshall

Publications and source records attributed to S Plaeger-Marshall.

At least 19 recordsLinked to original sources
PubMed1994

T cell activation in pediatric AIDS pathogenesis: three-color immunophenotyping.

Immune activation is an important component of HIV disease in adults that may reflect a protective host response and/or be a component of immunopathogenesis. The goals of this study were to gain understanding of T cell activation in pediatric HIV disease, to assess the usefulness of T cell activation markers as surrogates for disease progression and/or early identification of infection in infants at risk, and to determine any advantages of three- compared to two-color flow cytometric immunophenotyping for the above assessments. We examined the expression of cell-surface activation antigens on the CD4 and CD8 T cells of 26 HIV-infected and 40 HIV-seronegative age-matched control children. Compared with controls, HIV-infected children showed a slight but not significant decrease in the proportion of CD4 cells that coexpressed CD45RA and L-selectin (mean of 83 vs 75% for < 2 years of age, 76 vs 62% for 2-3 years, 64 vs 56% for > or = 4 years). CD4 cells coexpressing CD38 and HLA-DR were significantly increased in HIV+ children (mean of 2 vs 6% for < 2 years of age, 3 vs 11% for 2-3 years, 2 vs 8% for > or = 4 years). There was a striking and significant increase in the proportion of CD8 cells coexpressing CD38 and HLA-DR (mean of 5 vs. 25% for < 2 years, 10 vs 41% for 2-3 years, 6 vs 31% for > or = 4 years); this double positive population of CD8 cells included cells that were approximately 1 log brighter for the expression of CD38 than for that of CD38 single-positive cells. There was a significant reduction in CD45RA+ CD8 cells (means of 92 vs 71% for < 2 years of age, 88 vs 50% for 2-3 years, 80 vs 57% for > or = 4 years) and an increase in CD57+ CD8 cells (mean of 4 vs 8% for < 2 years of age, 8 vs 22% for 2-3 years, 19 vs 31% for > or = 4 years) in HIV+ children. The inclusion of CD3 as an anchor marker for CD8 cell subsets to limit the analysis to CD3+ CD8 cells did not substantially alter the data nor enhance the differences between infected and control children compared with the analysis of all CD8 cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1994

Comparison of cytotoxic properties of neonatal and adult neutrophils and monocytes and enhancement by cytokines.

We studied cytotoxic capabilities of newborn polymorphonuclear leukocytes (PMNs) and monocytes and their enhancement by cytokines and antibodies. Umbilical cord PMNs were assessed for their ability to kill various target cells spontaneously, after activation with phorbol myristate acetate, in the presence of antiserum (antibody-dependent cellular cytotoxicity), and in the presence of dually specific antibody (heteroantibody-mediated cytotoxicity). Target cells included the K562 cell line (natural killer cell target), chicken erythrocytes (CRBCs), and herpes simplex virus-infected CEM cell lines. Newborn PMNs were equivalent to adult PMNs in their cytotoxic capacity in several cytotoxicity assays. Neither adult nor newborn PMNs lyse tumor cell targets (i.e., K562 cells) spontaneously, but both lyse K562 cells following activation with phorbol myristate acetate. Both adult and newborn PMNs lyse CRBCs and herpes simplex virus-infected CEM cells in antibody-dependent cellular cytotoxicity assays, and this lysis could be enhanced by the cytokines granulocyte-macrophage colony-stimulating factor and gamma interferon. PMN heteroantibody-mediated cytotoxicity, resulting from the use of an antibody with dual specificity to CRBCs and immunoglobulin G FcRII, was greater in newborn PMNs than in adult PMNs; however, monocyte heteroantibody-mediated cytotoxicity, resulting from the use of an antibody to CRBCs and monocyte immunoglobulin G FcRI, was lower in newborn monocytes than in adult monocytes. The percentage, but not the density, of PMNs expressing FcRII was significantly reduced in newborn PMNs compared with that in adult PMNs, while the percentages and densities of FcRI expression were equivalent in newborn and adult monocytes. We conclude that the cytotoxic capability in term newborn PMNs is equivalent to that in adult PMNs, that the activity of newborn PMNs can be enhanced by antibody and/or cytokines, and that PMNs can contribute to the newborn's ability to kill virus-infected cells.

Adult↗
PubMed1993

Activation and differentiation antigens on T cells of healthy, at-risk, and HIV-infected children.

We examined the T-lymphocyte phenotypes of 67 human immunodeficiency virus (HIV)-infected children (P-1 or P-2) and 65 age-matched, healthy, control children stratified into four groups from < 1 to > or = 5 years of age to determine expression of antigens associated with cell activation/differentiation. Immunophenotyping was performed by laser flow cytometry using two-color immunofluorescent labeling. Although the control children showed a decline in total CD4 cell percent with age, the HIV-infected children in all age groups showed significantly decreased CD4 cell numbers compared with the age-matched controls. However, the slope of the CD4 cell decline with age was not significantly different in HIV-infected and control children. The CD4 cell decrease in infected children was reflected in both the CD45RA+ (naive) and CD45RA- (memory) CD4 cell subsets, although the CD45RA+ cells were decreased in greater proportion. Results assessing CD4 cells for expression of the L-selectin (Leu8) molecule were similar to those for CD45RA. The overall CD8 cell percentage was significantly increased in HIV-infected children compared with controls in all age groups. This was due primarily to increases in CD8 cells that were CD38+, CD57+, HLA-DR+, or CD45RA-. In a retrospective analysis of data from 23 P-0 children, we compared phenotype results from 5 children who were HIV+ with those 18 who were HIV-. Although the phenotypic changes seen in the 5 HIV+ children paralleled those described above for P-1 and P-2 subjects, there was no significant difference in the values for HIV+ compared with HIV P-0 children. Although the phenotypic alterations described did not appear to be diagnostic markers in P-0 children, they may serve as useful adjuncts for the evaluation of HIV-infected children.

ADP-ribosyl Cyclase↗
PubMed1991

Effects of herpes simplex virus on induced cell-mediated cytotoxicity in neonates and adults.

Deficient cellular cytotoxic mechanisms are present in neonates, contributing to their increased susceptibility to certain viruses, notably herpes simplex virus (HSV). Significant lymphokine-activated killer (LAK) cell activity has been described in cord blood, suggesting a possible role for LAK and/or interleukin-2 (IL-2) therapy in newborns with serious viral infections. The effect of HSV (type 1) on the activation of cord versus adult LAK cells was investigated by adding virus (multiplicity of infection, MOI = 10) to cells that had been previously incubated for 4-6 days with IL-2 (50-100 U/ml). The cells were then tested 24 h after virus exposure for cytotoxic activity against 51Cr-labelled K562 and Raji target cells. HSV inhibited LAK cytotoxicity of adult cells against K562 by 44% (72 +/- 2.4%, SEM; specific lysis to 40 +/- 6.2%, n = 15) and by 62% against Raji targets (50 +/- 5.6 to 19 +/- 4.4%). A similar degree of inhibition was observed for cord cells against K562 (76 +/- 2.0 to 46 +/- 5.3%) and Raji (60 +/- 4.6 to 24 +/- 6.2%). The degree of inhibition was correlated with the dose of virus in dose-response experiments. Inhibition was also noted with irradiated (10,000 rad) but not with heat-inactivated (56 degrees C for 60 min) virus. No inhibition was found when virus was added directly to the cytotoxic assay or when virus was added at the initiation or end of culture of cells with IL-2 (i.e. day 0 or day 5-7). In contrast, HSV stimulated cytotoxic activity against both the natural killer (NK)-sensitive (K562) and NK-resistant (Raji) targets in cells not incubated with IL-2. The cytotoxicity of adult cells incubated with infectious HSV (MOI = 10) for 5-7 days increased from 5.5 +/- 1.9% in the absence of virus to 25 +/- 6.0% against K562 in the presence of virus and from 3.5 +/- 1.0 (no virus) to 16 +/- 4.3% (with virus) against Raji targets (n = 8). The cytotoxicity of cord cells was also stimulated, but to a lesser degree. Irradiated virus also stimulated cytotoxic activity but to a lesser degree in cord cells. Virus-induced nonspecific cytotoxicity may represent an important component of the host's antiviral defense that is present at birth, but somewhat diminished compared to normal adults.

Antibodies, Monoclonal↗
PubMed1990

A clinical, hematologic, and immunologic analysis of 21 HTLV-II-infected intravenous drug users.

Infection with human T-cell leukemia virus type II (HTLV-II) has been associated with rare chronic T-cell malignancies and has recently been demonstrated in a significant proportion of American intravenous drug abusers (IVDA). Identification of an HTLV-II-infected cohort of IVDA has allowed analysis of the HTLV-II carrier state. We analyzed clinical, hematologic, and immunologic parameters in 21 HTLV-II-infected IVDA, two HTLV-I-infected IVDA, and 20 uninfected control IVDA identified by serologic screening and by analysis of peripheral blood mononuclear cell (PBMC) DNA by polymerase chain reaction (PCR). An elevated absolute lymphocyte count was observed in 4 of 21 HTLV-II-infected IVDA, 1 of 2 HTLV-I-infected IVDA, and 1 of 20 control IVDA. CD8+ T-cell elevation was observed in three of four HTLV-II IVDA with lymphocytosis and one of two HTLV-I-infected IVDA. Activation of CD8+ T cells in HTLV-II-infected IVDA was suggested by an overall increase in CD8+/HLA-DR+ lymphocytes. Cell fractionation and analysis by PCR of HTLV-II-infected carrier blood showed high levels of HTLV-II provirus in unfractionated PBMC and purified T cells and little or no detectable HTLV-II DNA in B cells or monocytes, indicating that T cells were the most likely target of infection in vivo. The frequency of HTLV-II-infected cells was estimated at approximately 1 in 500 cells or less using dilution analysis by PCR of PBMC DNA. Most HTLV-II-infected IVDA are asymptomatic and have no overt hematologic or immunologic abnormalities, although some manifest benign lymphocytosis.

Adult↗
PubMed1989

Lymphokine-activated killer cells in primary immunodeficiencies and acquired immunodeficiency syndrome.

Cytotoxic mechanisms (e.g., natural killer (NK) lysis, antibody-dependent cellular cytotoxicity, and cytotoxic T lymphocyte lysis) play an important role in host defense against various infections and neoplasms. Lymphokine-activated killer (LAK) cytotoxicity, induced in vitro by incubating mononuclear cells with interleukin 2 (IL-2) for 2-5 days, may also represent an important component of the body's cytotoxic repertoire. In 10 patients with congenital cellular immunodeficiencies, including 5 with severe combined immunodeficiency, the mean LAK activity in a 3-hr chromium release assay against Raji target cells was 44 +/- 8.1%, which is equivalent to that observed in normal adults and neonates. In only one case, a patient with reticular dysgenesis, was there absent LAK cell generation. Haploidentical T cell-depleted bone marrow transplantation (BMT) restored LAK activity in this patient. LAK activity was first observed in this patient and two others 3-6 weeks following BMT, prior to other evidence of immunologic engraftment such as lymphocyte proliferation to mitogens, NK activity, or interferon-gamma production. One patient with adenosine deaminase deficiency showed normal levels of LAK activity despite absent NK activity. Three patients with chronic granulomatous disease also had normal LAK activity (57 +/- 14% specific lysis). In 9 patients with acquired immunodeficiency syndrome (AIDS), IL-2 activation resulted in a mean cytotoxic activity of 56 +/- 8.7% toward Raji targets. In addition, 9 patients with pre-AIDS complex also showed normal levels of cytotoxicity (37 +/- 3.3% toward Raji targets), equivalent to that of 8 normal controls, including two healthy homosexual males (mean lysis 38 +/- 3.9%). These results indicate that LAK cells appear early in immunologic ontogeny. Further, the mechanism of lysis is not oxygen dependent since LAK activity was present in the 3 patients with chronic granulomatous disease. The ability to generate LAK in a wide spectrum of immunodeficiencies may indicate that IL-2 could be used in therapy of such disorders.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Lymphocyte function in major depression.

Immunologic function as measured by lymphocyte response to phytohemagglutinin (PHA) mitogen was evaluated in 8 psychiatric inpatients. All were less than 45 years of age and had a DSM-III diagnosis of major depression. When patient's immunologic responses were compared with healthy age- and sex-matched controls, a significant increase in PHA mitogen stimulation was observed in the depressed group. Further, a significantly greater variance in PHA response was observed in the patients compared with controls. The literature on depression and immunity is reviewed and the clinical implications of our findings are discussed.

Adult↗
PubMed1989

Replication of herpes simplex virus in blood monocytes and placental macrophages from human neonates.

Increased permissiveness of macrophages for herpes simplex virus (HSV) replication may be a mechanism for the dissemination and severity of neonatal herpetic infection. We have assessed the replication of HSV in neonatal blood monocytes and placental macrophages using several criteria for viral permissiveness. Assay of production of infectious progeny virus indicated that cord blood monocytes, like adult monocytes, were nonpermissive for HSV (about 1% of cells producing virus). In vitro culture of cord blood monocytes resulted in increased replication of HSV, but no greater extent than virus production in cultured adult cells. HSV infection of fetal placental macrophages was weak but present (4.4% of cells). Assay of production of viral antigens and electron microscopic analysis of structural elements indicated that a larger number of cord blood monocytes and placental macrophages were abortively infected than were productively infected. These results indicate that monocytes and macrophages from human neonates do not show the enhanced permissiveness for HSV demonstrated in newborn mice and suggest that dissemination of herpetic infection in human newborns cannot be explained by increased neonatal monocyte permissiveness for HSV.

DNA Replication↗
PubMed1988

Interferon-induced expression of class II major histocompatibility antigens in the major histocompatibility complex (MHC) class II deficiency syndrome.

Class II antigens encoded by genes of the major histocompatibility complex (MHC) are expressed by a variety of cell types and have a vital role in the cellular interactions required for an effective immune response. We have analyzed the regulation of HLA-DR, DP, and DQ class II antigen expression on cells of different lineage from an immunodeficient patient with the MHC class II deficiency syndrome. T and B lymphocytes, monocytes, and fibroblasts, which initially expressed no class II antigens, were treated with inductive stimuli that normally lead to enhanced expression of class II antigens. Monocytes, but not fibroblasts, cultured for 48-96 hr in the presence of recombinant gamma interferon expressed all three types of class II antigens. In contrast, T lymphocytes did not express class II antigens following their exposure to a variety of stimuli, including activation with phytohemagglutinin and culture in the presence of interleukin-2, transformation by the retrovirus HTLV-1 or HTLV-2, or exposure to the demethylating agent 5-azacytidine. Similarly, class II antigens were not induced on B cells by cross-linkage of surface immunoglobulin molecules with anti-mu, exposure to Epstein-Barr virus, or treatment with soluble factors secreted by activated T cells. These results demonstrate that the regulation of class II MHC antigen expression by monocytes and lymphocytes is dissimilar and suggest that different regulatory genes are involved in the control of class II antigen expression by cells of different lineage.

Adult↗
PubMed1988

Abnormal differentiation of immunoregulatory T-lymphocyte subpopulations in the major histocompatibility complex (MHC) class II antigen deficiency syndrome.

The major histocompatibility complex (MHC) class II deficiency syndrome is a rare immunodeficiency disease associated with defective expression of class II MHC antigens. We have examined the consequences of this defect for the differentiation and functional capabilities of immunoregulatory T-cell subpopulations in an affected patient. Although the number of circulating T cells was normal, there was a striking reduction in the number of CD4+ T cells. Furthermore, purified CD4+ cells from the patient were unable to provide help for antibody secretion. This defect in helper function appeared to be due to the abnormal differentiation of the few CD4+ cells present, virtually all of which expressed the CD4+HB11+ phenotype characteristic of immature "virgin" T cells. Abnormal development of immunoregulatory CD8+ T cells was also observed. Although increased numbers of CD8+ T cells were present, virtually none had phenotypic properties of suppressor cells (i.e., CD3+/CD8+/9.3- granular lymphocytes that coexpress the Leu-15 or Leu-7 antigens), and purified CD8+ cells from the patient had no suppressor activity. Thus, the absence of class II MHC antigens profoundly disrupts the development of immunoregulatory T cells. We propose that these effects occur by the following mechanisms: (1) the absence of intrathymic class II antigens results in deficient production of CD4+ cells, (2) the CD4+ cells that do emerge from the thymus do not undergo postthymic maturation into CD4+HB11- cells with helper capabilities, and (3) the absence of CD4+HB11- effector cells results in abortive development of suppressor cells involved in feedback suppression.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Bare lymphocyte syndrome. Consequences of absent class II major histocompatibility antigen expression for B lymphocyte differentiation and function.

The bare lymphocyte syndrome is a rare combined immunodeficiency disorder associated with the absence of class I and/or class II major histocompatibility (MHC) antigens. Although it has been inferred that the immune deficiency is a consequence of disordered MHC-restricted interactions among otherwise normal cells, the biological capabilities and differentiation of B lymphocytes deficient in class II MHC antigens have not been rigorously analyzed. We have examined the phenotypic and functional attributes of B cells with absent class II MHC antigens. Our data demonstrate that these B cells are intrinsically defective in their responses to membrane-mediated activation stimuli. In addition, virtually all the B cells had phenotypic evidence of arrested differentiation at an immature stage. Finally, these B cells also failed to express the C3d-EBV receptor normally present on all B lymphocytes. These data indicate that class II MHC molecules are vital participants in early events of the B cell activation cascade, and that other non-MHC membrane molecules may also be absent as a consequence of either arrested differentiation or as a result of the basic defect affecting the expression of MHC membrane antigens.

Antibody-Producing Cells↗
PubMed1988

Surface antigens of theophylline-resistant and theophylline-sensitive human E rosette-forming T lymphocytes.

Theophylline-resistant (TER) and theophylline-sensitive (TES) subsets of E rosette-forming T cells were analysed for surface antigens detected by monoclonal antibodies Leu-2, Leu-15, Leu-3, and Leu-8. Two-colour analysis was performed by laser flow cytometry. About 30% of TER cells was classified as Leu-2+, 15- precursor cytotoxic T lymphocytes and about 50% as 3+,8+ (T inducers). TES fraction was deficient in cytotoxic 2+,15- cells and contained lymphocytes belonging to suppressor circuit. Leu-3+,8- (helpers and suppressor-amplifiers) were present in both fractions.

Antibodies, Monoclonal↗
PubMed1987

Alterations in cytotoxic and phenotypic subsets of natural killer cells in acquired immune deficiency syndrome (AIDS).

Testing of cytotoxic function using a panel of natural killer (NK)-sensitive target cells, including a unique herpes simplex virus-infected Raji-cell target, was performed in conjunction with phenotypic cell analysis by dual-color flow cytometry to characterize the NK system. Subjects included in the study were at risk for or infected with the etiologic agent of the acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV). A generalized defect in NK function was temporally correlated with disease manifestations, as evidenced by deficient NK lytic function in patients with AIDS and AIDS-related complex (ARC). Healthy at-risk subjects, including those seropositive for HIV, exhibited robust NK-cell function. Phenotypic analysis revealed that normal proportions of the NK-associated CD16+ (Leu11) Leu7- and CD16+(Leu11)Leu7+ lymphocyte subsets were maintained throughout the clinical progression of HIV infection. However, the proportion and numbers of cells of the CD8+(Leu2)Leu7+ subset were increased in AIDS, ARC, and healthy at-risk subjects, including those seronegative for HIV. These results are consistent with a qualitative defect in the NK system in AIDS, perhaps secondary to CD4-cell depletion and a concomitant lack of essential accessory factors. The elevation in CD8+(Leu2)/Leu7+ cells is not solely the result of HIV infection and may be a general response to viruses and/or other antigenic stimulation.

AIDS-Related Complex↗
PubMed1986

A statistical method for assessing change in immunologic parameters in a patient.

Serial measurement of in vitro immunologic parameters in patients is used to detect change in immune status over time due to disease progression and/or immunodulatory therapy. A statistical method is presented for looking at serial measurements on an individual to detect whether a change in a parameter is outside the bounds of expected within-individual variation. Analysis of variance is used, assuming a normal distribution, to obtain percentiles of the distribution of the absolute difference between consecutive values of immunologic parameters in a healthy population. The assumptions in this analysis are justified from a statistical point of view. We discuss how to use this statistical method to make judgments relevant to clinical immunology, including how to construct a table that can be used to determine quickly if an "interesting" change for some standard immunologic parameters has occurred, whether a linear (additive) or logarithmic (proportional) model for change might be more appropriate for a given parameter, and how to modify the calculations if change is expected in a certain direction or if multiple pre- and/or postevent (clinical change or intervention) measurements are available.

Adult↗
PubMed1985

Influence of racial background on the distribution of T-cell subsets and Leu 11-positive lymphocytes in healthy blood donors.

As part of a study to define the factors affecting the distribution of lymphocyte subpopulations in healthy blood donors, we have measured lymphocyte surface markers in various racial groups. Markers tested were T3 (all T cells), T4A (T helper cells), T8 (T suppressor cells), and Leu 11 (natural killer cells). Racial groups included three Asian groups (Chinese, Japanese, Other Orientals) and three non-Asian groups (Caucasians, Hispanics, American Blacks). The mean percentage of T3 + cells and T4A + cells were significantly lower in Asians compared with non-Asians, while T8 levels did not differ. These changes resulted in a significantly lower mean T4A:T8 ratio in Asians compared with non-Asians. The mean percentage of Leu 11 + cells was higher in Asians compared with non-Asians. Within the Asian group, Chinese had a higher mean Leu 11 + value than the other two Asian groups combined. Further, pairwise comparisons showed that Chinese had a significantly higher mean Leu 11 + value compared with each of the other five racial groups. This increased mean Leu 11 + level in the Chinese group reflected a distinct cluster of high values for about half the subjects. These findings show that racial background should be a major consideration when defining the normal range for lymphocyte subpopulations detected by surface markers.

Adult↗
PubMed1983

Alteration of rabbit alveolar and peritoneal macrophage function by herpes simplex virus.

Exposure of rabbit alveolar and peritoneal macrophages to infectious herpes simplex virus resulted in inhibition of antibody-dependent cellular cytotoxicity and either enhancement or inhibition of phagocytosis. At all times after exposure, virus was inhibitory to peritoneal macrophage phagocytosis. Alveolar macrophages showed enhanced phagocytic activity in the early stages of virus exposure and inhibition at later time points.

Animals↗