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Biomedical subjects

M Feldmann

Publications and source records attributed to M Feldmann.

At least 343 records · Page 19Linked to original sources
PubMed1984

The relationship between secreted and cell surface antigen-binding molecules synthesized by T cells. I. Function-related isotypic determinants on T cells defined by antisera to antigen-specific helper and suppressor factors.

Rabbit antisera have been used to define 'constant region' markers which distinguish between mouse T cell-derived helper and suppressor factors, regardless of their antigen-specificity or strain of origin. These antisera have also been shown to bind to functional T-cell lines. After several absorption steps, rabbit anti-helper factor serum bound specifically to mouse helper cell lines, whereas rabbit anti-suppressor factor serum bound specifically to suppressor cell lines. Neither antiserum bound to cytotoxic T cell lines. The 'isotypic' determinants defined by these antisera were demonstrated to be present on distinct subpopulations of non-transformed T cell populations, such as splenic T cells, cortisone-resistant thymocytes and Con A blasts, but were not found on Thy-1- spleen cells, bone marrow, brain, heart, liver, kidney or heart tissue. The antisera did not stain significant numbers of normal thymocytes, and so expression was restricted to mature T cells. T cells reactive with rabbit anti-helper factor serum were found in the Lyt 2- population of cortisone-resistant thymocytes, and constituted a major subpopulation of in vitro induced helper cells, while rabbit anti-suppressor factor serum stained cells found in the Lyt 2+ population of cortisone-resistant thymocytes, as well as the majority of in vitro induced suppressor cells. Thus, these antisera are potentially of great value in the definition and isolation of functionally-distinct T cell subpopulations.

Animals↗
PubMed1984

Clonal approaches to immune regulation by lymphocytes.

Analysis of immune regulation has been greatly facilitated by the development of clones of antigen reactive T cells. We have been analysing the regulation of these clones both by antigen, and by other cells, and review here the salient features of regulation of helper clones. Antigen at high concentrations may induce tolerance in a helper clone, in the absence of other T cells or accessory cells. This process was markedly antigen dose and time dependent, specific, and lasted at least 7 days. A key features was that response to TCGF was not altered. These experiments indicate that suppressor cells need not be involved in all forms of tolerance, and that antigen can interact directly with T cells. Regulation by an autologous anticlone raised by in vitro immunization of PBL with an irradiated clone is discussed. Its specificity for the immunizing clone suggests that it may recognize receptors, and suppressor clones of this type may be a possible strategy for regulating unwanted clones of lymphoid cells in autoimmunity or leukaemias. The implications of these findings for cancer in general are discussed.

Animals↗
PubMed1983

Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity.

Immune responses are initiated by HLA-DR+ cells, which present antigen to T cells. Observations that HLA-DR may be experimentally induced on thyroid epithelium and that HLA-DR occurs on thyrocytes in autoimmune thyroid diseases suggest a mechanism of autoimmunity with special relevance to organ-specific diseases. This involves the local aberrant expression of HLA-DR antigens by epithelial cells and their subsequent capacity to present autoantigens occurring on their surfaces to T lymphocytes. For autoantigens which T cells recognise infrequently because of their restricted tissue location and low concentration in the circulation, T-cell tolerance is unlikely, and so induction of autoreactive T cells would occur. Because interferon is the best known inducer of DR antigen expression and viral infections may predate endocrine autoimmunity, the following sequence seems likely: local viral infection which causes interferon production, or other local environmental factors which would induce DR expression, presentation of autoantigens, and subsequent autoimmune T-cell induction. These T cells would activate effector B and T cells. Whether the initial induction of autoimmune T cells leads to autoimmune disease would depend on factors such as abnormalities of the suppressor T-cell pathway, reported to coexist with autoimmunity and necessary to induce autoimmune disease in mice. This mechanism of autoimmune disease induction explains vague associations with viral infections and long latency periods before disease becomes manifest and gives a simple explanation for the well-documented association between HLA-DR and autoimmune diseases in man.

Autoantigens↗
PubMed1983

Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin.

Antigen-specific human T cell clones specific for defined peptides of influenza A hemagglutinin were found to be rendered unresponsive by incubation with moderately high concentrations of antigen. This was the case whether the synthetic peptide antigen was present for the duration of the culture or the cloned T cells were preincubated with antigen for 3-18 h at 37 degrees C, before stimulation with T-depleted irradiated sheep erythrocyte non-rosette-forming lymphocytes (E-) pulsed with the optimal dose of peptide. Tolerance could not be overcome by culture with various numbers of E- cells and antigen. The induction of unresponsiveness was antigen specific, since it depended upon incubation with the appropriate peptide recognized by that clone. In addition, the tolerant T cells remained unresponsive to stimulation with the specific peptide for at least 7 d after induction even though maintained in culture in the presence of T cell growth factor. This state of antigen-specific unresponsiveness is akin to immunological tolerance. Furthermore, the experiments reported here demonstrate that the helper T cell clone can be inhibited by the relevant peptide in the absence of any suppressor cells or their precursors. This suggests that antigen-induced unresponsiveness need not always depend on the presence of suppressor T cells. The induction of tolerance in T cell clones does not result in early T cell death, since cells that no longer proliferate in response to the specific antigen and accessory cells still proliferate in response to T cell growth factor.

Antibodies, Viral↗
PubMed1983

A monoclonal antibody against antigen-specific helper factor augments T-cell help.

Antigen-specific molecules, commonly termed 'factors', have been shown to be released from helper and suppressor T cells. These factors mimic the activity of the cells that secrete them and there is much speculation about the relationship of antigen-specific factors to T-cell receptors for antigen. We have raised a variety of antisera in rabbits which were shown to react against conserved 'constant' determinants on either helper or suppressor factors independently of antigenic specificity or mouse strain of origin of the factor. In contrast, syngeneic mouse antisera were found to react with 'variable' factor determinants in an antigen-specific and mouse strain-dependent manner. These antisera thus define two regions on factor molecules, one 'variable' (related to antigen specificity) and the other 'constant' (related to function). However, potential contaminants in these antisera have limited their usefulness. Thus, we are now generating monoclonal antibodies against T-cell factors and report here the properties of a monoclonal antibody (AF3.44.4) which reacts with antigen-specific helper factors. This antibody also binds to helper T cells and, in the presence of antigen, augments helper cell induction in vitro, which, in turn, leads to enhanced antibody production in vitro. These characteristics suggest that AF3.44.4 recognizes a determinant shared by helper factor and the antigen receptor on helper T cells.

Animals↗
PubMed1983

The dissociation of interleukin-2 production and antigen-specific helper activity by clonal analysis.

Influenza virus immune human T-lymphocyte clones maintained in continuous culture in TCGF were analysed for helper activity and interleukin-2 (IL-2) production. The clones that functioned as helper cells in the production of specific antibody failed to release detectable amounts of IL-2. Conversely, the T cells that produced IL-2 were unable to provide either specific or non-specific helper function. These findings indicated the IL-2 is not an essential component for helper activity. However, phenotypic analysis revealed that both the functional subsets of T-cell clones expressed the helper phenotype in that they were T4+, T3+ and T11+. Nevertheless analysis with other antibodies revealed differences in that the IL-2 releasing clone showed greater staining with the anti-T-cell subset antibodies 9.3 and Leu 8, confirming that there is phenotype as well as functional heterogeneity within the helper inducer T-cell population.

Antibodies, Viral↗
PubMed1983

Induction of a T-cell mediated suppressor activity by soluble products from antigen-specific helper/inducer human T-cell lines.

Influenza virus-specific (A/X31) long-term cultured human T-cell lines belonging to the helper/inducer T-cell set, produce high potency antigen specific helper factors which induce in vitro antibody production to A/X31 by autologous B cells, as well as small and variable amounts of non-specific helper factors. When added to unseparated peripheral blood mononuclear cells, both cultured T cells and their supernatants suppress in vitro antibody synthesis as measured by a solid phase enzyme-linked immunoassay, and T-cell proliferation to antigens and allogeneic cells, but not to mitogens. This phenomenon was further analysed and could be separated into several steps: (i) the production of suppressor inducer factor(s) by the T-cell lines which are distinct from the helper molecules; (ii) activation of T cells belonging to the suppressor/cytotoxic subset as defined by monoclonal antibodies, a process which is antigen-independent and non-genetically restricted, and is optimal with 18 hr incubation; (iii) the activated T cells non-specific suppress antibody production and antigen-induced or allogeneic cell-induced T-cell proliferation. Thus, antigen-specifically activated T-inducer cells exert multiple activities, including specific and non-specific help and non-specific induction of T suppressor cells.

Antibodies, Viral↗
PubMed1983

Antigen-specific and non-specific helper activities derived from supernatants of human influenza virus-specific T-cell lines.

A T-cell line (H3) was established by culturing human peripheral blood mononuclear cells with influenza virus A/X31 and maintained in long term culture with Interleukin-2 (TCGF). Supernatants were prepared by culturing these cells overnight in the absence of Interleukin-2 but with A/X31 and irradiated autologous E rosette negative cells as a source of antigen presenting cells, and harvesting by centrifugation. The supernatants were shown to replace T cells in helping E- (B) cells to produce antibody specific to A/X31 which was measured by enzyme immunoassay (EIA). Although maximal help was obtained with autologous or semi allogeneic B cells (in the latter case bearing HLA-DR 3 loci) there was still significant antibody production with allogeneic combinations. The supernatants were subsequently fractionated into specific and non-specific helper activities by gel filtration, giving an approximate mol. wt of 50-70,000 and 10-30,000 for each respectively. The specific HF was shown to be genetically restricted in its action upon B cells and also to generate antibody to A/X31 only. The lower molecular weight material acted on any responding B cell regardless of HLA-DR type and produced antibody non-specifically in culture with E- cells even in the absence of antigen. The apparent lack of restriction was therefore due to the masking effect of non-specific and non-restricted HF(s) on the genetically restricted specific HF produced by this line.

Antibodies, Viral↗
PubMed1982

An influenza virus matrix protein-specific human T cell line with helper activity for in vitro anti-hemagglutinin antibody production.

A human helper T cell line (F14m) activated by the matrix protein purified from A/X31 influenza virus has been developed. After activation by antigen for 7 days, and reculture with matrix protein and irradiated autologous feeder cells, the cells obtained from an in vivo influenza virus-immunized donor have been growing in the presence of interleukin 2 for more than 7 months. The cells all belong to the helper-inducer T cell subset and most of them express surface membrane HLA-DR antigens. A small number (approximately 10(3)) of F14m T cells provided optimal help for 1 X 10(5) autologous T-depleted lymphocytes for production of anti-A/X31 but not anti-B/HK antibodies. The F14m T cells produce soluble factors (S14m) able to help B cells to secrete anti-A/X31 antibodies. F14m and S14m were shown to help antibody production to hemagglutinin when cultured with B cells and the whole virus. The specificity of the T cell line for type-A matrix protein was confirmed by the ability of S14m to provide help for anti-A/JAP (A/H2/N2) but not for anti-B/HK antibody production. These data provide evidence for matrix protein-specific T helper cells and factors able to provide help for antibody production against hemagglutinin, a distinct protein of the same virus.

Antibodies, Monoclonal↗
PubMed1982

Specific suppression of antibody responses in vivo. I. Effects of in vitro produced suppressor factor.

KLH-specific suppressor factors produced in vitro efficiently diminished primary and secondary responses to trinitrophenyl keyhole limpet haemocyanin (TNP-KLH) in vivo. Both IgM and IgG responses were approximately equally affected, These suppressor factors were not genetically restricted, as allogeneic suppressor factors worked as efficiently as syngeneic factors. Furthermore, xenogeneic human suppressor factors were effective in mice and suppressed the responses as efficiently as syngeneic factors. The kinetics of the response in suppressed and non-suppressed mice was the same, indicating that the magnitude of the response was affected and not merely its time course. Prior injection with suppressor factor did not cause suppression of response, while suppressor factor injected at the same time as or soon after the antigen did, suggesting that it might act at the effector stage. The mechanism of action of this unrestricted suppressor factor, and the use of mouse model for in vivo testing of human suppressor factors is discussed.

Animals↗