Biomedical subjects

S Myrdal

Publications and source records attributed to S Myrdal.

10 recordsLinked to original sources

PubMed1996

Intracellular CD22 rapidly moves to the cell surface in a tyrosine kinase-dependent manner following antigen receptor stimulation.

CD22 is a key accessory molecule for Ag receptor signaling in B cells that becomes tyrosine phosphorylated in the signaling process. CD22 associates with sIg and strongly amplifies sIg-induced signals. During B cell development, CD22 is initially expressed intracellularly, with surface expression appearing with IgD expression. We used confocal laser-scanning microscopy and flow cytometry to analyze CD22 translocation responses to signaling events. Cross-linking surface IgM (sIgM) induced rapid movement of CD22 to the cell surface in both Ramos and Daudi B cells, with a 50 to 100% increase in surface expression observed within 5 min of stimulation. The increase in CD22 surface expression was specific in that CD19 expression was not affected. Both cell surface and intracellular CD22 were directed toward the site of sIgM stimulation. Treatment with the phosphotyrosine phosphatase inhibitor bis(maltolato)oxovanadium(IV) also increased CD22 surface expression. The tyrosine kinase inhibitor tyrphostin A10 inhibited CD22 movement at concentrations that inhibited tyrosine phosphorylation of CD22 and other cellular proteins. In contrast to the B cell lines, mature peripheral blood B cells contained very little intracellular CD22 and showed no significant increase in surface expression following sIgM stimulation. The rapid directed movement of intracellular CD22 provides a new mechanism to dynamically regulate Ag receptor signaling, as well as CD22-mediated adhesion.

Antigens, CD↗

PubMed1995

Lineage-specific induction of B cell apoptosis and altered signal transduction by the phosphotyrosine phosphatase inhibitor bis(maltolato)oxovanadium(IV).

Protein tyrosine phosphorylation is known to play key roles in lymphocyte signal transduction, and phosphotyrosine phosphatases (PTP) can act as both positive and negative regulators of these lymphocyte signals. We sought to examine the role of PTP further in these processes by characterizing the effects of bis(maltolato)-oxovanadium(IV) (BMLOV), previously known to be a nontoxic insulin mimetic agent in vivo. BMLOV was found to be a potent phosphotyrosine phosphatase inhibitor. BMLOV induced cellular tyrosine phosphorylation in B cells in a pattern similar to that observed following antigen receptor stimulation, whereas little tyrosine phosphorylation was induced in T cells. In B cells, BMLOV treatment resulted in tyrosine phosphorylation of Syk and phospholipase C gamma 2, while sIgM-induced signals were inhibited. By contrast, T cell receptor signals were moderately increased by BMLOV, and the cells displayed greater induction of IL-2 receptor without toxicity. The compound selectively induced apoptosis in B cell lymphoma and myeloid leukemia cell lines, but not in T cell leukemia or colon carcinoma cells. Interleukin-4 plus anti-CD40 antibody treatment of normal human peripheral B cells rescued the cells from BMLOV-induced death. These results suggest that phosphotyrosine phosphatase inhibitors can activate B cell signal pathways in a lineage-specific manner, resulting in desensitization of receptor-mediated signaling and induction of apoptosis.

Animals↗

PubMed1994

Costimulation of T lymphocytes with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induces functional expression of CTLA-4, a second receptor for B7.

Costimulation by the CD28 ligand B7/BB1 plays an important role during T cell proliferation primarily by augmenting synthesis of IL-2 and other cytokines. Resting CD4+ T cells express CD28 but not CTLA-4 on their surface. Costimulation of T cells with ICAM-1 or VCAM-1 induced CTLA-4 expression and up-regulated CD28 expression. CD28 and CTLA-4 were independently distributed on the surface of activated T lymphoblasts. When co-immobilized with anti-TCR mAb both anti-CD28 and anti-CTLA-4 mAb augmented T cell proliferation. Although anti-CD28-mediated augmentation of T cell proliferation was stronger than that seen with anti-CTLA-4 mAb, together these two mAb caused supraadditive augmentation of T cell proliferation. The augmentation of the effects of anti-CD28 mAb by anti-CTLA-4 mAb was greater at low occupancy of CD28 by anti-CD28 mAb. Costimulation of CD28+ CTLA-4+ T cells with anti-CTLA-4 caused three- to fivefold increase in IL-2 production, whereas similar treatment with anti-CD28 caused > 40-fold increase. The costimulatory effect of B7 on primed T cells was partially inhibited by Fab anti-CD28 mAb. Anti-CTLA-4 mAb alone did not inhibit B7-induced response but caused modest increase in the inhibitory effect of anti-CD28 Fab. On integrin-mediated costimulation, Ag-specific CD4+ T cell lines also up-regulated their CTLA-4 expression, and proliferation of these cells was augmented by anti-CTLA-4 mAb. Unlike that of CD28, ligation of CTLA-4 alone failed to mobilize intracellular [Ca2+]. However, coligation of CTLA-4 and TCR induced stronger [Ca2+] response in Ag-specific T cell lines than that seen with TCR alone. These results suggest that integrin-costimulated T cells express CTLA-4 and can be costimulated via CTLA-4. Optimal development of various immune functions may involve combined costimulation via both CD28 and CTLA-4.

Abatacept↗

PubMed1992

T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo.

Organ graft rejection is a T-cell-dependent process. The activation of alloreactive T cells requires stimulation of the T-cell receptor/CD3 complex by foreign major histocompatibility complex (MHC)-encoded gene products. However, accumulating evidence suggests that, in addition to T-cell receptor occupancy, other costimulatory signals are required to induce T-cell activation. Previously, the CD28 receptor expressed on T cells has been shown to serve as a surface component of a signal transduction pathway that can provide costimulation. In vitro, interaction of CD28 with its natural ligand B7 expressed on the surface of activated B cells or macrophages can act as a costimulus to induce proliferation and lymphokine production in antigen receptor-activated T cells. We now report evidence that stimulation of T cells by the CD28 ligand B7 is a required costimulatory event for the rejection of a MHC-incompatible cardiac allograft in vivo. These results demonstrate that the B7/CD28 activation pathway plays an important role in regulating in vivo T-cell responses.

Animals↗

PubMed1987

The effect of epidermal growth factor on chronotropic response in cardiac cells in culture.

Cardiac chronotropic response to epidermal growth factor (EGF) was assessed in chick embryonic ventricular cell aggregates. EGF at a concentration of 10 ug/mL but not at 5 ug/mL produced a significant (p less than 0.05) increase in cardiac beating rate. This was evident within 10 min, reached a peak at about 15 min and remained at that level for 1.5 hr or the rest of the observation period. The effect of EGF on cardiac automaticity was reduced but not abolished at a lower temperature (22oC) that is known to decrease the affinity of the EGF receptor and reduce the internalization of EGF. Hypothermia did not change the maximum increase in heart rate response from isoproterenol although it altered the pattern of the response. Beta adrenoreceptor blockade with metoprolol only slightly altered the response to EGF. These data indicate that EGF produces functional effects on the heart that may be mediated through EGF receptor linked mechanisms.

Animals↗

PubMed1986

Regional variations in tuberculosis policy in the Cape and Ciskei.

Regional variations in tuberculosis policy in Cape Town, Paarl and Ciskei, as well as problems experienced by health workers, are examined. South African policy is compared with modern trends and recommendations drawn from the international literature and is found to conform in many respects, although tuberculosis services are not always integrated with curative services. The most marked variation occurs in Ciskei, where policy requires hospitalization of as many patients as possible. The majority of problems in implementing policy relate to lack of funds and medical infrastructure.

Drug Therapy, Combination↗

PubMed1986

The implementation of tuberculosis policy in three areas in South Africa.

The implementation of tuberculosis policy at hospital and clinic level was examined in three areas (Cape Town, Paarl and Ciskei). Investigation showed that bacteriological diagnosis, standardized treatment regimens, supervision of therapy and contact tracing were not being correctly implemented. Compliance was also poor.

Adolescent↗

PubMed1986

Tuberculosis--the patients' perspective.

This, the last of three studies examining aspects of tuberculosis (TB) control in South Africa, ascertained the views of the consumer--the TB patient. Aspects such as the impact of contracting TB on employment opportunities and social life, difficulties in getting treatment, and knowledge of TB were studied in a sample population of urban black working-class TB patients. Patients had difficulties in getting treatment at centralized points, and health education was not effective. Poor socio-economic conditions were also important in the experience of the TB sufferer.

Adolescent↗

PubMed1985

Attitudes to the provision of primary health care at the day hospitals in Cape Town.

Day hospitals in Cape Town are examined against the criteria in the definition of primary health care of the World Health Organization's Declaration of Alma Ata. A survey of patients attending a day hospital was undertaken to ascertain the consumer perspective regarding access to and quality of the service offered. The provider's perspective was obtained from secondary sources and in-depth interviews. It was found that the services are generally acceptable to the users, but that factors such as waiting time and transport create problems for patients. Community participation is also very limited. The separation of preventive and curative services also places limitations on the day hospitals--they provide only curative health care. The most important reason given by patients for using the day hospitals is the low cost.

Adolescent↗

PubMedDate not supplied

Time-resolved confocal analysis of antibody penetration into living, solid tumor spheroids.

The in vivo function of a biologically active molecule is governed in part by the dynamics of its distribution within its target tissue. To enhance our ability to probe living cells, we have endeavored to improve live confocal microscopy methods and to develop analytical methods that simplify the handling of the resulting complex data sets. To do this we attached a recently developed micro-incubation system to the stage of a Leica confocal laser scanning microscope and were able to maintain physiologic culture conditions over several hours. Axial stability was achieved by modifying the room air conditioning. Laser illumination was low enough to retain cell viability through several hours of continuous scanning. With this setup, planar, time-resolved data sets (xyt) were produced by continuously rescanning a single xy plane at the rate of one scan/min. As an alternative, volumetric data sets (xyz) were acquired by stepping the scanned plane through the z axis. In both types of data sets, a semi-quantitative determination of the concentration of a fluorescent reporter molecule (e.g., FITC) over a gray level range of 0.255 was recorded along with the positional information. Thus, concentration (as intensity of fluorescence, or i) gave a fourth variable by either scan method, resulting in high-density xyti or xyzi data sets. The biological model we used to examine these methods was the penetration of a FITC-labeled, anti-carcinoma monoclonal antibody into cultured spheroids of tumor cells bearing the antibody-binding epitope. In one case, the distribution of antibody-FITC conjugate was compared with that of a long wavelength membrane dye, DiIC18(5). Several different software analyses were compared, including examining xyt data sets as "volumes". We observed that by increasing the displayed resolution of one variable, the demonstrable resolution of the other variables was reduced. For example, with high temporal resolution, either quantitative or positional resolution had to be sacrificed. Thus, we needed to perform several different analyses of a single data set to compare all of the variables properly. In these experiments, the dynamic aspects of the changes in antibody-FITC distribution were examined. Along with comparison of antibody-FITC penetration with that of DiI, these data suggest an as yet unexplained biological transport of antibody into a tumor spheroid, which is not consistent with mere passive diffusion through the fluid of extracellular clefts. Using this model system, we have performed and analyzed highly time-resolved confocal microscopy on living specimens maintained under physiologic conditions.

Adenocarcinoma↗