Biomedical subjects

D R Katz

Publications and source records attributed to D R Katz.

At least 73 records · Page 4Linked to original sources

PubMed1991

Antigen presentation by dendritic cells provides optimal stimulation for the production of interleukin (IL) 2, IL 4 and interferon-gamma by allogeneic T cells.

Previous studies have shown that dendritic cells are the most potent inducers of T cell proliferation in vitro and that this is reflected in the release of interleukin (IL) 2 into culture supernatants during dendritic cell-T cell interaction. However, the role of the dendritic cells, and, indeed, of the antigen-presenting step, has not yet been explored with respect to other T cell-derived cytokines, in either a qualitative or relative fashion. In this study, therefore, we have examined the comparative role of different antigen-presenting cells (APC) as inducers of T cell cytokine release in allogeneic responses. We have confirmed that dendritic cells are the most effective inducers for IL2 and have shown that this is true not only in primary alloresponses, but also in alloresponder T cells maintained for extended periods and then rechallenged. Dendritic cells were also the most potent inducers of IL3 and interferon-gamma (IFN-gamma) in primary cultures. No IL4 was demonstrable irrespective of the type of presenting cells used, and both tissue macrophages and dendritic cells can induce synthesis of IL6. Likewise, in secondary alloresponses both dendritic cells and to a lesser extent tissue macrophages induce release of IL3, no IL4 is detectable, and activated macrophages and B cells raise IFN-gamma levels in the supernatants albeit to a lower concentration than that seen when dendritic cells are used as stimulators. The results were similar in the tertiary alloresponse except that (a) IL4 was now detectable in the supernatants but only where dendritic cells had been used as APC, and (b) both resting and activated macrophages induced IL2 and IFN-gamma. By the eighth cycle of allostimulation there is negligible IL2. Dendritic cells, tissue macrophages and activated B cells constitute a hierarchy of APC for IL3, IFN-gamma and IL4. These findings therefore demonstrate the role of dendritic cells as potent in vitro inducers of IL3, IL4 and IFN-gamma synthesis as well as of IL2.

Animals↗

PubMed1991

The c-fgr proto-oncogene: expression in Epstein-Barr-virus-infected B lymphocytes and in cells of the myelomonocytic and granulocytic lineages.

The c-fgr proto-oncogene, which is a member of the c-src gene family, encodes the cytoplasmic tyrosine kinase p55c-fgr. Expression of the c-fgr gene is activated in human B lymphocytes following infection with Epstein-Barr virus, and the viral protein EBNA-2 is involved in mediating this effect. The only normal cells in which the c-fgr gene is known to be expressed are peripheral-blood granulocytes and monocytes, and tissue macrophages. In accordance with this, levels of c-fgr mRNA increase when the human promonocytic cell line U937 and the human myelomonocytic cell line HL60 are induced to differentiate. The enzyme activity and the expression pattern of p55c-fgr suggest that it is involved in regulating the responses of terminally differentiated granulocytes and monocytes to external stimuli, perhaps by controlling changes in cytoskeletal structure.

B-Lymphocytes↗

PubMed1991

1,25(OH)2D3 regulates c-myc mRNA levels in tonsillar T lymphocytes.

The effects of 1,25(OH)2D3 on proliferation, c-myc mRNA levels and 1,25(OH)2D3 receptor expression in activated tonsillar T lymphocytes were studied. Activation of resting T cells with phytohaemagglutinin (PHA) for 72 hr led to an increase in proliferation, c-myc mRNA levels and to induction of 1,25(OH)2D3 receptor expression. However, when activation was carried out in the presence of 1,25(OH)2D3, there was inhibition of PHA-stimulated proliferation and c-myc mRNA levels. Increased cell proliferation, c-myc mRNA expression and 1,25(OH)2D3 receptor number were also observed, albeit to a lesser extent, when T cells were stimulated by phorbol myristate acetate (PMA), anti-CD3 antibody or A23187. However, in these cases 1,25(OH)2D3 was unable to prevent increased proliferation or c-myc mRNA expression. PMA and anti-CD3 used in combination produced similar or greater changes in proliferation, c-myc mRNA levels, 1,25(OH)2D3 receptor expression and responsiveness to the hormone when compared to PHA alone. Thus the inhibition of c-myc expression in activated T lymphocytes by 1,25(OH)2D3 can be related to its anti-proliferative effects. Moreover this inhibition seems to be dependent on the level of 1,25(OH)2D3 receptor expression, which in turn appears to be related to the degree of cell activation.

Calcitriol↗

PubMed1990

The role of CD44, CD45, CD45RO, CD46 and CD55 as potential anti-adhesion molecules involved in the binding of human tonsillar T cells to phorbol 12-myristate 13-acetate-differentiated U-937 cells.

In this study, we have shown that human tonsillar T cells adhere to phorbol 12-myristate 13-acetate(PMA)-differentiated U-937 cells. To examine the molecular mechanisms involved, the effect of a panel of monoclonal antibodies upon this adhesion was assessed in a quantitative binding assay. Antibodies against LFA-1 and ICAM-1 inhibited binding, directly implicated these molecules in T cell-PMA-induced U-937 adhesion. Furthermore, the adhesion was magnesium but not calcium dependent. Of the remaining antibodies that were tested, none of those against CD2, LFA-3, Mac-1, p150,95, CD43, CD45RA or CD56 affected binding. However, antibodies against CD44, CD45, CD45RO, CD46 and CD55 enhanced binding suggesting an anti-adhesive role for these molecules during U-937-T cell interaction.

Antigen-Presenting Cells↗

PubMed1990

Mononuclear phagocytes and HSV-1 infection: increased permissivity in differentiated U937 cells is mediated by post-transcriptional regulation of viral immediate-early gene expression.

Undifferentiated U937 cells are non-permissive for herpes simplex virus (HSV) infection but can be rendered permissive by treatment with phorbol myristate acetate (PMA), which causes them to differentiate to a macrophage-like phenotype. Following infection with HSV, both PMA--treated and untreated cells correctly transcribe the viral immediate-early genes at levels comparable to those observed in fully permissive cell types, but immediate-early RNA and protein are detected only in the PMA-treated cells. Hence PMA acts by relieving an early block to HSV infection caused by the rapid turnover of immediate-early RNA. This block is not caused by the production of soluble inhibitors and can also be relieved by treatment with other agents that cause macrophage differentiation such as 1, 25 dihydroxycholecalciferol. These findings therefore indicate that the non-permissivity of undifferentiated U937 cells for HSV is mediated by post-transcriptional regulation of immediate-early gene expression.

Cell Line↗

PubMed1990

Mechanisms of dendritic cell function.

There is now considerable evidence, from in vivo and in vitro studies, supporting the claim that dendritic cells are the principal accessory cells of the vertebrate immune system. Until recently, however, the biology of the dendritic cell accessory mechanism has remained obscure. Here, Philip King and David Katz review recent findings that have clarified several aspects of this mechanism, providing a possible basis for the potent T-cell stimulating capacity of the dendritic cell, and yielding clues to the ontogenetic relationships of these cells and to their role in immunopathology.

Animals↗

PubMed1990

Intermittent hypercalcaemia and vitamin D sensitivity in Hodgkin's disease.

A patient with Hodgkin's disease spontaneously developed steroid-responsive hypercalcaemia during two consecutive summers. Administration of 3000 U/day of vitamin D, while he was normocalcaemic, caused a sharp increase in serum 1,25(OH)2D3 (from 59 pg/ml to 142 pg/ml) and subsequently hypercalcaemia while serum 25(OH)D3 rose moderately within the normal range (from 2.8 ng/ml to 10 ng/ml). During a spontaneous episode of hypercalcaemia which was accompanied by increased circulating 1,25(OH)2D3 concentrations, administration of hydrocortisone decreased serum 1,25(OH)2D3 rapidly (from 115 pg/ml to 62 pg/ml) and eventually led to normocalcaemia while serum 25(OH)D3 remained unchanged. Thus the disturbances of mineral metabolism found in this patient with Hodgkin's disease are very similar to those previously described in sarcoidosis.

Aged↗

PubMed1990

Cytomegalovirus in the lungs of patients with AIDS. Respiratory pathogen or passenger?

A total of 166 consecutive clinical episodes of pneumonitis in patients with acquired immune deficiency syndrome (AIDS) or antibody positive for human immune deficiency virus (HIV) were investigated for evidence of cytomegalovirus (CMV) infection in their lungs and at peripheral sites to determine the pathogenicity of this virus in the lung and its relationship to peripheral CMV shedding. Evidence of CMV infection was sought in bronchoalveolar lavage (BAL) fluid, blood, saliva, and urine using a specific monoclonal antibody to antigens produced by CMV-infected cells within 24 h. Although CMV was detected in 31 (19%) of BAL fluid specimens, in only six episodes was this the sole pathologic finding. In the remaining episodes either another infectious agent, Kaposi's sarcoma, or lymphoid interstitial pneumonitis was found or no pathogen was detected. None of the patients were given specific anti-CMV treatment, and all but two recovered, including those patients in whom CMV was the sole finding at BAL. The presence of peripheral shedding of CMV did not have any significance in mortality or morbidity. Our findings are in direct contrast to those in recipients of allogeneic bone marrow transplants, in whom CMV pneumonitis is associated with a high mortality. We postulate that this difference is because AIDS patients cannot mount the destructive immune response to CMV in the lung, which we believe to be the basis of the pathology seen in the former group. We conclude that CMV is not a pathogen in the lungs of patients with HIV infection, and we suggest that its presence at this site does not warrant specific therapy in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

PubMed1989

Human tonsillar dendritic cell-induced T cell responses: analysis of molecular mechanisms using monoclonal antibodies.

Dendritic cells, isolated from human tonsillar tissue, were found to be potent stimulators of the sodium periodate T cell oxidative mitogenesis reaction. Monoclonal antibodies against CD2, CD4, CD11a, CD18, LFA-3, ICAM-1, class I and class II major histocompatibility complex (MHC) inhibited T cell proliferation in this response, whereas antibodies against CD8, CD11b, CD11c and CD16 had no effect. Further, antibodies against CD2, CD11a, CD18, LFA-3 and ICAM-1 inhibited the early dendritic cell-T cell clustering event which occurs in this cell interaction. In contrast, antibodies against CD4, class I and class II MHC did not inhibit clustering. Studies examining the expression of the respective molecules upon isolated dendritic cells and T cells suggest that anti-LFA-3 and anti-class II MHC antibodies inhibit at the level of the dendritic cell, whereas anti-CD2 and anti-CD4 antibodies inhibit at the level of the T cell. However, antibodies against CD11a, CD18, ICAM-1 and class I MHC may inhibit at either or both cell levels. These findings have enabled us to propose a molecular mechanism for dendritic cell-T cell interaction in oxidative mitogenesis. Dendritic cell-T cell clustering is mediated by bidirectional binding of LFA-1 (CD11a and CD18) and ICAM-1 (involving both molecules on both cell types) and unidirectional binding of CD2 and LFA-3 (involving T cell CD2 and dendritic cell LFA-3). This initial event permits a second interaction of dendritic cell and T cell molecules, involving T cell CD4, class I MHC (possibly at both cellular levels) and dendritic cell class II MHC, which deliver the signal for proliferation.

Antibodies, Monoclonal↗

PubMed1989

Modulation of myelomonocytic U937 cells by vitamin D metabolites.

Investigation of the effects of 1,25(OH)2D3 and 24,25(OH)2D3 on the proliferation and differentiation of the human myelomonocytic cell line U937 has been complemented with studies of the effect of the same metabolites on the number of nuclear receptors for 1,25(OH)2D3. Both 1,25(OH)2D3 and 24,25(OH)2D3 inhibit the proliferation of U937 cells in a dose-dependent manner. The concentrations of 24,25(OH)2D3 required to produce this effect were 100-times greater than those of 1,25(OH)2D3. Inhibition of proliferation was associated with increased expression of the CD14 and 200 kDa 63D3 antigens thus confirming differentiation of U937 towards a more mature cell type. Studies of the nuclear receptor for 1,25(OH)2D3 showed that pre-treatment of the cells with 1,25(OH)2D3 resulted in an apparent 40% decrease in the number of detectable 1,25(OH)2D3 receptors as compared to control U937 cells. This is due to the fact that the 1,25(OH)2D3 binds to U937 cell nuclei during culture and thus blocks the subsequent binding of radiolabelled 1,25(OH)2D3 used to measure the number of 1,25(OH)2D3 receptors. Measurement of the binding of unlabelled 1,25(OH)2D3 by radioimmunoassay indicated that pre-treatment of the cells with 1,25(OH)2D3 increased the capacity of U937 to bind the hormone, although measurement of these receptors by whole cell assay was prevented by the binding of 1,25(OH)2D3 itself. This effect was not observed with 24,25(OH)2D3 which was more easily displaced from binding sites by radiolabelled 1,25(OH)2D3 and it appears to act through low affinity binding to the 1,25(OH)2D3 receptor.

24,25-Dihydroxyvitamin D 3↗

PubMed1989

Autocrine regulation of 1,25-dihydroxycholecalciferol metabolism in myelomonocytic cells.

In this study the effects of vitamin D metabolites on the myelomonocytic precursor cell line U937 have been compared with those of phorbol myristate acetate (PMA). PMA was used as a cell modulating agent in order to avoid effects of binding of the exogenous vitamin D metabolites receptors within the cell, which would interfere with subsequent measurement of these receptors in studies of the vitamin D3 metabolic pathway. Both the active 1,25 DHCC form of vitamin D3 and the inactive 24,25 DHCC metabolite inhibit cell proliferation and induce 24-hydroxylase activity, but not 1 alpha-hydroxylase activity. These effects are dose-dependent and maximum enzyme activity is seen in the adherent cell population, which is induced by these compounds. PMA inhibits proliferation of U937 and increases receptors for 1,25 DHCC in these cells (like the vitamin D metabolites). However, unlike the vitamin D metabolites, PMA induces 1 alpha-hydroxylase activity rather than 24-hydroxylase activity. Thus, while PMA and 1,25 DHCC have some similar effects on monocyte precursor cell line differentiation, there is a difference between the effects of the two agents on the vitamin D metabolic pathway. The former promotes synthesis of the active metabolite, and the latter induces an enzyme which renders the metabolite inactive. If these results are considered together, they are consistent with the hypothesis that 1,25 DHCC has an autocrine role within the mononuclear phagocyte system.

Calcitriol↗

PubMed1988

Antigen presentation, antigen-presenting cells and antigen processing.

To summarize, during the period under review there have been considerable advances in our understanding of how antigen is associated with MHC on the surface of a presenting cell. Basic rules which govern this association have been confirmed as including both the nature and the configuration of the antigen. Although the different processing pathways which generate the antigen-MHC complex have remained ill-defined, it is now much more clear what the optimum end point of such processing must be. As a result of these studies, several new questions can now be addressed in the field of antigen presentation. During the next few years it should become apparent why there should be such an unusual differential presenting cell requirement for T cells which are expressing a selected variable region of the T cell receptor and whether other T cells expressing different receptors have different optimum presentation requirements. It should become clear also whether different antigens have similar residues at the sides of the alpha helix which are important in MHC binding, and whether the sheet or helix models are more important in vivo. A rational explanation for dominance of alloreactivity has been proposed, and kinetic studies of self-MHC processing are essential to define this further. Furthermore the possibility of an antigen unmasking an MHC polymorphism (which in turn could influence presentation) will have to be considered seriously in the pathogenesis of auto-immunity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Human T-cell activation: comparative studies on the role of different phorbol esters.

We confirm here previous studies that have shown synergy between anti-CD3 and phorbol esters in the induction of T-cell proliferation. However, for this study we have used tonsillar rather than peripheral blood T cells, and have compared the role of different phorbol esters rather than different anti-CD3 antibodies in the activation process. Three phorbol esters (phorbol myristate acetate, -dibenzoate and -didecanoate) showed a synergistic relationship. However, the concentration of the dibenzoate and the didecanoate forms required was higher than the concentration of myristate acetate. A second group of phorbol esters (alpha-phorbol didecanoate, a beta phorbol with no side chain, and a monomyristate) did not activate T cells. This difference in activation efficiency between the phorbol derivatives correlates with the pattern of neutrophil activation that has been described previously using the same compounds. In contrast to both the neutrophil and the proliferation studies, if the T cells were preincubated with the different phorbol esters and then subsequently cultured with anti-CD3, the pattern of response was different. Only phorbol myristate acetate induced a proliferative response; all the other compounds were inactive. Taken in conjunction with the known structural differences between the different phorbol derivatives, these results suggest that the relative lipophilic properties of the different molecules which activate T cells may be an important determinant in the induction of a response. Thus changes in the relative lipophilic properties of an antigen could be one way to alter its relative immunogenicity.

Antibodies, Monoclonal↗

PubMed1988

Induction of delayed-type hypersensitivity responses to PPD: dendritic cells in synergy with 5-hydroxytryptamine can substitute for macrophages.

We describe the use of 5-hydroxytryptamine (5HT) as an adjuvant in the induction of the delayed-type hypersensitivity (DTH) response to purified protein derivative (PPD). Based upon our previous studies with antigen-pulsed macrophages (M phi), we have shown that both the Day 2 early (2 hr) reaction and the Day 3 (24 hr) reaction are augmented if 5HT is incorporated into the priming injection. Furthermore, we have confirmed that in contrast to M phi, antigen-pulsed dendritic cells (DC) fail to prime the early (2 hr) component of DTH. However, DC do prime the early response if injected along with 5HT. A peripheral 5HT antagonist, ICS 205-930, inhibits both the M phi-mediated and the 5HT/DC-primed reactions. These findings support the hypothesis that DTH reactions require a cascade of both inflammatory and immunological signals, and that in mice vascular permeability mediated via 5HT is important in the early phase of the reaction.

Adjuvants, Immunologic↗

PubMed1987

Vitamin A acetate as a regulator of accessory cell function in delayed-type hypersensitivity responses.

Mice fed on a vitamin A acetate (VAA)-supplemented diet respond to concentrations of oxazolone which are too low to elicit contact sensitivity on a standard diet. This study has investigated whether enhanced responsiveness could be due to VAA-induced changes in antigen-presenting cell function. The draining lymph nodes were used as the source for accessory cell populations, and cells from control and sensitized mice on either standard or VAA diet were compared in syngeneic and allogeneic responses. Their ability to induce delayed-type hypersensitivity reactions was also compared. There was no qualitative difference between accessory cells from the standard and VAA-fed groups respectively, but there was already a striking quantitative increase in the number of accessory cells which correlated with augmented sensitization. These findings are consistent with the postulate that the effect of VAA may be associated with regulation of accessory cell function, and that susceptibility to contact sensitization can be modified by quantitative changes in antigen presentation.

Adjuvants, Immunologic↗

PubMed1987

Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol.

Dendritic cells have been isolated from human tonsillar tissue and shown to act as accessory cells in a mitogenic response. The dendritic cells will induced receptors for the active metabolite of vitamin D3, 1,25(OH)2D3, in the responder E+ T cells. The dendritic cells themselves constitutively express receptors for the metabolite, and this distinguishes them from other non-T cells in lymphomedullary tissue. Expression of the 1,25(OH)2D3 receptor may be a dendritic cell property that facilitates their accessory cell role within the tissue microenvironment.

Calcitriol↗

PubMed1987

Regulation of accessory cell function by retinoids in murine immune responses.

This study examines the effects of in-vivo immune regulation by vitamin A acetate (VAA) and 13-cis-retinoic acid (13-CRA) on in-vitro accessory cell function. Mice were fed a control diet, or diet containing VAA or 13-CRA, and monitored by body weight gains and diet consumptions at weekly intervals. At 4, 7 and 12 weeks mice were killed, differential blood counts performed and accessory cells isolated from lymphomedullary tissues. Histology confirmed that the chief feature of the lymphomedullary organs of the VAA-fed animals was an expansion of the splenic marginal zone and the paracortical region of the lymph nodes. There was an increase in the number of accessory cells present, and this included both dendritic cells and macrophages. The accessory cell function of these cells was also increased, as evidenced by both alloproliferative and allocytotoxic responses in vitro. In 13-CRA-fed animals the effects were similar to those seen with VAA, but were less pronounced. We suggest that the primary effects of these compounds on in-vivo immunoregulation could be due to their promotion of accessory cell function.

Animals↗

PubMed1986

Heterogeneity of accessory cells interacting with T-helper clones.

We have investigated the comparative role of dendritic cells and macrophages as inducers of proliferative responses in antigen-specific T-helper lines and clones grown in serum-free medium. Dendritic cells are the most potent accessory cells for both soluble (ovalbumin-specific) and particulate (horse red blood cell-specific) lines. However, at the clonal level there is heterogeneity. Individual clones will respond to antigen presented on either dendritic cells or macrophages, respectively. Synergy between the two accessory cell types was not demonstrable. Depletion of cells that express Class II antigens from the macrophage population abrogated the proliferative response. These findings confirm heterogeneity of the accessory cell pool, and support the suggestion that this accessory cell heterogeneity may be one of the selective mechanisms that determine T-cell responses at the clonal level.

Animals↗