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Biomedical subjects

M Feldmann

Publications and source records attributed to M Feldmann.

At least 325 records · Page 18Linked to original sources
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↗
PubMed1986

The cellular pathway of antigen presentation: biochemical and functional analysis of antigen processing in dendritic cells and macrophages.

The response of primed T cells to keyhole limpet haemocyanin (KLH) was used to compare the characteristics of antigen presentation by lymphoid dendritic cells, splenic and peritoneal macrophages. In a similar manner to macrophages, purified dendritic cells could be pulsed with antigen and subsequently fixed by brief glutaraldehyde fixation and still retain antigen presenting activity. Also, as previously reported for macrophages, presentation could be inhibited by chloroquine. These functional experiments suggested that the pathway of antigen presentation in dendritic cells and macrophages was similar or identical. However, biochemical studies, using radiolabelled antigen, showed that dendritic cells do not significantly degrade large proteins such as KLH to TCA-soluble form, but partially hydrolyse them to smaller peptide fragments. The significance of these results in terms of a model of the cellular pathways of antigen presentation is discussed.

Animals↗
PubMed1986

Regulation of macrophage accessory cell activity by mycobacteria. II. In vitro inhibition of Ia expression by Mycobacterium microti.

In our preceding study, we showed that infection of mice with Mycobacterium microti leads to a dramatic increase in Ia expression on local inflammatory macrophage populations. However, the majority of these cells did not contain intracellular organisms. To evaluate the effect of parasitism of macrophages by M. microti, Ia-induction experiments were performed in vitro. We show here that Ia expression is increased on peritoneal macrophages treated with either crude lymphokine preparations or recombinant gamma-interferon (gamma-IFN) and that this expression is suppressed by M. microti in a dose dependent fashion. The degree of suppression varied between macrophage populations and could be achieved to a lesser extent with killed organisms. It was partially reversed with indomethacin but only poorly so at high infection levels. Inhibition of Ia expression may be of importance in the generation and maintenance of chronic infection.

Animals↗
PubMed1986

Inappropriate major histocompatibility complex class II expression by thyroid follicular cells in thyroid autoimmune disease and by pancreatic beta cells in type I diabetes.

"Inappropriate" expression of class II major histocompatibility complex (MHC) molecules by target cells has been found in all organ-specific autoimmune diseases so far examined for the presence of this phenomenon. These glycoproteins may have a functional role as class II+ thyrocytes are able to present both small fragments of foreign antigens and autoantigens to helper T cells. Interferon gamma is a likely modulator of MHC class II expression in the thyroid but other signals like thyroid-stimulating hormone seem to influence its action. By contrast, it appears that lymphokines are not involved in inducing the inappropriate MHC class II expression observed in situ in the pancreatic beta cells of diabetics. These data suggest that regulation of MHC class II expression is different in thyroid follicular cells from pancreatic beta cells, and that similar differences may be found in other cell types involved in autoimmune disease, thus reinforcing the concept of heterogeneity in the pathogenesis of organ-specific autoimmune disorders.

Antigen-Presenting Cells↗
PubMed1986

Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas.

Inappropriate expression of HLA Class II (D/DR) molecules has been detected in the target cells of most autoimmune diseases including Type I (insulin-dependent) diabetes. The possibility that this phenomenon is due to the action of lymphocytes or some of their products has been investigated by analysing in vitro the modulation of HLA products in Beta cells. Monolayer cultures from 25 human pancreatic glands were supplemented with alpha-interferon (IFN), beta-IFN or gamma-IFN, interleukin 2 (IL-2) and supernatants from activated lymphocytes. In addition, lectins and a variety of other hormones, biological products and chemicals were tested. Major histocompatibility complex (MHC) expression was assessed by double immunofluorescence technique using monoclonal antibodies to non-polymorphic determinants of Class I and Class II molecules and the pancreatic cells were identified by antibodies to islet hormones and other cytoplasmic antigens. gamma-IFN and lectins produced a parallel enhancement of HLA-A,B,C expression in islet, exocrine/ductal cells and fibroblasts. HLA-D/DR was inducible in all pancreatic cell types, except endocrine islet cells which did not produce Class II molecules in response to any of the stimuli including supernatants from activated lymphocytes. Exocrine/ductal cells from glands of patients with chronic pancreatitis spontaneously expressed Class II products, but islet cells were devoid of any detectable D/DR. These data are consistent with recent observations which have indicated that in the 'diabetic' pancreas inappropriate Class II expression in the Beta cells occurs independently of the presence of lymphocytes infiltrating the islets, and make it necessary to postulate that other factors are responsible for the Class II induction in Beta cells in human Type I diabetes.

Cells, Cultured↗
PubMed1986

Regulation of macrophage accessory cell activity by mycobacteria. I. Ia expression in normal and irradiated mice infected with Mycobacterium microti.

CBA/Ca mice were infected by either the intravenous or intraperitoneal route with Mycobacterium microti and the subsequent changes in local macrophage populations examined. Following infection, the number of macrophages increased and they showed greater expression of both MHC Class II molecules. This response was not dependent on viability of the mycobacteria, in contrast to reports with other microorganisms such as Listeria. Studies in sublethally irradiated mice indicated that persistent antigen could give rise to a response after a period of host recovery which was radiation dose dependent. This procedure also highlighted differences in the regulation of different murine class II antigens in vivo, as seen by delayed re-expression of I-E antigens. Macrophage accessory cell function, as assessed by an in vitro T cell proliferation assay, correlated with Ia expression after fixation, but not after indomethacin treatment; this highlights the diverse nature of regulatory molecules produced by these cells.

Animals↗
PubMed1985

Human T-cell clones from autoimmune thyroid glands: specific recognition of autologous thyroid cells.

The thyroid glands of patients with autoimmune diseases such as Graves' disease and certain forms of goiter contain infiltrating activated T lymphocytes and, unlike cells of normal glands, the epithelial follicular cells strongly express histocompatibility antigens of the HLA-DR type. In a study of such autoimmune disorders, the infiltrating T cells from the thyroid glands of two patients with Graves' disease were cloned in mitogen-free interleukin-2 (T-cell growth factor). The clones were expanded and their specificity was tested. Three types of clones were found. One group, of T4 phenotype, specifically recognized autologous thyroid cells. Another, also of T4 phenotype, recognized autologous thyroid or blood cells and thus responded positively in the autologous mixed lymphocyte reaction. Other clones derived from cells that were activated in vivo were of no known specificity. These clones provide a model of a human autoimmune disease and their analysis should clarify mechanisms of pathogenesis and provide clues to abrogating these undesirable immune responses.

Animals↗
PubMed1985

Biochemical events initiated by exposure of human T lymphocyte clones to immunogenic and tolerogenic concentrations of antigen.

Interleukin 2-dependent helper T cells, cloned from human peripheral blood lymphocytes activated with strain A influenza virus hemagglutinin, proliferate in response to a 24-residue synthetic peptide (p20) of hemagglutinin, but become unresponsive to a subsequent immunogenic challenge when pretreated with a high concentration of p20. This phenomenon is associated with a loss of the T3 antigen complex, presumably in association with the T cell receptor. We have examined this phenomenon in more detail and show that in addition to changes in the expression of T3 molecules on the cell surface, high doses of p20 cause changes in the expression of certain biosynthetically and surface-labeled proteins, although total DNA and protein synthesis was unaltered. Thus, by examining these biochemical phenomena we can begin to define some of the processes which occur during antigen activation of human T lymphocytes at the clonal level.

Antigens, Surface↗
PubMed1985

Augmentation of cell-mediated responses in vitro by a monoclonal anti-helper factor antibody.

Previous studies have shown that monoclonal antibody AF3.44.4 has specificity for a constant region determinant on mouse antigen-specific helper factors and that it also binds to cultured T cells with functional helper cell characteristics. The antibody synergizes with antigen to enhance in vitro antibody responses; here we demonstrate that it will also enhance cell-mediated responses in vitro such as in the generation of proliferating cells in mixed lymphocyte responses and in the generation of specific killer cells in cytotoxic T lymphocyte cultures. The mechanism of AF3.44.4-generated enhancement was investigated. Increased levels of the lymphokines IL-2 and BCDF were detected in supernatants of AF3.44.4-treated cultures but the antibody itself could not replace interleukin-2 (IL-2), and would not stimulate primed cells in the absence of antigen. This type of monoclonal antibody which augments immunological responses in an antigen-dependent fashion may provide a new class of immunostimulant and a new approach to augmenting the responses of weak immunogens.

Animals↗
PubMed1985

Nonphagocytic dendritic cells are effective accessory cells for anti-mycobacterial responses in vitro.

The accessory cell requirements for a given T cell response may be examined in vitro by using highly purified lymph node T cells. We have examined the capacity of different antigen-presenting cells to stimulate proliferation of Mycobacterium tuberculosis-primed T cells when the antigenic challenge is either soluble or particulate in nature. By titrations of cell number and antigen concentration, it was shown that dendritic cells are not only extremely efficient at presenting soluble mycobacterial antigen compared with various macrophage populations, but also that they are capable of presenting whole mycobacteria. Because phagocytosis of mycobacteria does not occur with these cells, we suggest that processing of antigen by dendritic cells may be initiated at the plasma membrane. Because macrophages are not essential for this in vitro response, a role for dendritic cells in antibacterial immunity in vivo is implicated.

Animals↗
PubMed1985

The distribution of interleukin-2 receptor bearing lymphocytes in multiple sclerosis: evidence for a key role of activated lymphocytes.

The identification of T cells in the brain using monoclonal antibodies has suggested a role for T cells in the pathogenesis of multiple sclerosis (MS). In the present study the monoclonal antibody anti-Tac, shown to react with interleukin-2 (IL-2) receptors expressed on activated T cells, was used to determine levels of recently activated T cells in blood, cerebrospinal fluid (CSF) and brain sections from MS patients at different stages of disease. The CSF of MS patients contained much higher numbers of IL-2 receptor positive lymphocytes (up to 67%) than blood cells from the same patients, or the CSF of patients with non-inflammatory neurological diseases. In histological sections of the brain of MS patients with active disease, perivascular lymphocytes expressing IL-2 receptors were detected, as were lymphocytes containing IL-2. In contrast, these were absent in brain sections from patients with chronic MS, secondary demyelination or from normal controls. These observations in CSF and brain suggest that in multiple sclerosis, T-cell activation is occurring within the CNS and not in peripheral lymphoid tissue.

Antibodies, Monoclonal↗
PubMed1985

Interferon-gamma induces HLA-DR expression by thyroid epithelium.

We recently showed that human thyroid epithelial cells, which are normally negative for HLA-DR molecules, express HLA-DR in thyroid autoimmunity. Furthermore, induction of HLA-DR on normal thyroid cells can be achieved by culture with plant lectins. We have now found that recombinant human interferon-gamma (IFN-gamma) induces expression of HLA-DR molecules on cultured human thyroid cells, whereas Namalva IFN-alpha, recombinant IFN-beta or recombinant interleukin-2 (IL-2) do not. All three IFN, but not IL-2, enhanced thyroid cell HLA-A,B,C expression. The results strongly implicate T cells (which are the source of IFN-gamma) in the aberrant induction of DR on thyroid epithelial cells which is proposed to be a central feature of the immunopathological processes leading to autoimmunity.

Cells, Cultured↗
PubMed1984

Inhibition of T cell proliferation by antibodies to synthetic peptides.

While T cell proliferation to antigen in the presence of antigen-presenting cells is well known to be readily inhibited by antibodies directed against Class II major histocompatibility complex (MHC) (Ia/HLA-DR) products, it has not been possible to inhibit proliferation by antibodies directed against the antigen. Because of the implications of these observations for targets of T cell recognition, this phenomenon was reinvestigated using human T cell clones, recognizing a small (24 amino acid) synthetic peptide (termed p20) derived from the influenza hemagglutinin-1 molecule. It was found that proliferation of clones to p20 was inhibited efficiently (less than 90%), using p20 as antigen, and rabbit anti-p20. Inhibition was possible either by coculturing p20 antigen and antibody to p20 with cloned T cells and antigen-presenting (E-) cells, or by pulsing antigen-presenting cells with antigen prior to a brief incubation with antibody before washing the E- cells and using them to stimulate cloned T cells. These results do not indicate why previous attempts had failed, but in view of the different techniques available now (cloned T cells, small synthetic polypeptides, and antibody raised against polypeptide) we investigated the influence of these parameters. It was found that, using cloned T cells, the form of the antigen was of importance, as antibody inhibition of the response to hemagglutinin or whole influenza A was much less apparent. These differences were interpreted as being due to greater access of anti-p20 to p20 than to hemagglutinin or influenza. If uncloned T cell lines were used, inhibition was also much harder to detect. This was interpreted as masking of inhibition of the response of some clones in the line by interleukin 2-induced recruitment.

Animals↗
PubMed1984

Direct evaluation of antigen binding to human T lymphocyte clones: involvement of major histocompatibility complex products in antigen binding.

Cloned human helper T lymphocytes reactive with a defined peptide (p20; residues 306-329) of the HA-1 molecule of influenza virus hemagglutinin were analyzed for their capacity to specifically bind peptide antigen. Three different methods of analyzing antigen binding to T cell receptors were compared. One method involved the binding of radiolabeled T cells to antigen-pulsed populations of sheep erythrocyte rosette-negative (E-) cells (B cells and monocytes). The binding was antigen specific, in that only E- cells pulsed with the appropriate antigen bound the treated T cells, and was inhibitable by free peptide. Furthermore, antigen binding was major histocompatibility complex-restricted in that only E- cells histocompatible at the HLA-D region locus bound the T cells, and monoclonal antibody of the relevant specificity was able to inhibit the binding. Secondly, it was demonstrated that tritiated T cells could bind to insolubilized antigen (p20) in the absence of E- cells. The binding was inhibited by anti-class II antibody suggesting that the interaction of antigen with the T cells involves recognition of T cell major histocompatibility complex class II determinants. Finally, radiolabeled peptides were also used to detect binding to the appropriate clones in the absence of presenting cells. This binding was specific, inhibitable by the appropriate unlabeled peptide and temperature dependent. These studies demonstrate that the process of antigen binding to receptors is analyzable and should in turn facilitate the analysis of the mechanism of T cell activation.

Antigen-Presenting Cells↗