Biomedical subjects

M Feldmann

Publications and source records attributed to M Feldmann.

At least 271 records · Page 15Linked to original sources

PubMed1989

Analysis of T-cell receptor usage in activated T-cell clones from Hashimoto's thyroiditis and Graves' disease.

Rearrangements to the T-cell receptor (TcR) beta and gamma gene loci were studied in T cells derived from the thyroid glands of a patient with Hashimoto's (HT) and another with Graves' (GD) autoimmune thyroiditis. The cells studied were freshly isolated mononuclear cells, T-cell lines grown in the presence of anti-CD3 and IL-2 and T-cell clones. Numerous different rearrangements to the constant regions of TcR beta and TcR gamma and in the variable gene region of TcR beta were observed. These findings indicate that the T-cell response in autoimmune thyroiditis is multiclonal and may have implications for the epitopes recognized by autoreactive T cells and for the mechanisms of the disease.

Adult↗

PubMed1989

T-cell clone anti-clone interactions. Effects on suppressor and helper activities.

An experimental model of two interacting clones of T cells is described, which may be used for defining and exploring the T-cell immunoregulatory network. Mx9/9 is a CD4 clone bearing an antigen receptor recognized by the Mx9 anti-V beta 8 monoclonal antibody (MoAb). Anti-V beta 8 MoAbs activate and induce cell proliferation of this clone. Autologous clones were raised against Mx9/9 cells using the peripheral blood mononuclear (PBM) cells of the Mx9/9 clone donor (PBMjm). Some of these cloned anti-clone cells proliferated after stimulation with irradiated Mx9/9 cells, but not after stimulation with other autologous cloned T cells or heterologous PBM, suggesting that these clones recognize the T cell receptor (TCR) of the Mx9/9 cells. The proliferation of the Mx9/9 stimulated cloned anticlone cells was blocked by anti-class II MoAbs, indicating that the autoreactive clones recognize their target antigen in conjunction with HLA Class II products. The ability of clone Mx9/9 to proliferate after stimulation with anti-V beta 8 MoAb was inhibited when clone 121 cells were added to the cultures. However, clone 121 lost its suppressor function after 4 months in culture and instead gained the ability to enhance the proliferation of Mx9/9 cells in the presence of anti-V beta 8 MoAb. In contrast, clone 18 lacked suppressor activity at the early stage of the study but later acquired this function. We conclude that some autoreactive clones are not fully committed and may express more than a single function. Such cells cannot therefore be designated as 'suppressor cells', although they expressed suppressor potential at certain stages.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1989

Intrathyroidal cytokine production in thyroid disease.

The intrathyroidal production of Interferon gamma, tumour necrosis factor alpha and beta, Interleukin-1 alpha and beta, Interleukin-6, platelet-derived growth factor A and of transforming growth factor-beta was analysed in patients with autoimmune and non-autoimmune thyroid disease. Cytokines were assessed indirectly by slot blot mRNA analysis in fresh tissue samples (unpurified cells, infiltrating mononuclear cells and thyroid follicular cells), in thyroid follicular cells in primary culture, as well as in thyroid-derived T-cell clones. The production of Interleukin-1 alpha and beta, Interleukin-6 and transforming growth factor beta was additionally measured by bioassay. Cytokine production by thyroid-infiltrating mononuclear cells generally did not differ between autoimmune and non-autoimmune samples, the whole panel of all cytokines being found in freshly purified cells as well as in thyroid-derived T-cell clones from patient with Graves' disease, as well as with multinodular non-toxic goitre. Thyroid follicular cells produced Interleukin-1 alpha, Interleukin-6 and transforming growth factor beta. Interleukin-1 and Interleukin-6 production did not differ between thyroid follicular cells from autoimmune and non-autoimmune thyroids. Transforming growth factor beta was, however, lower in non-toxic goitre than in Graves' disease and in normal thyroid tissue, but could be increased by exposure of the cells to micromolar concentrations of iodide. This seemed of special interest, as transforming growth factor beta proved to inhibit thyroid follicular cell growth in response to known growth stimuli, such as insulin-like growth factor I or epidermal growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune Diseases↗

PubMed1989

Cytokine production in culture by cells isolated from the synovial membrane.

Cytokine expression was investigated in synovial cell cultures isolated from diseased joints of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Tumour necrosis factor alpha (TNF alpha) was produced spontaneously at high levels by both RA and OA synovial cells. There was no correlation between cell composition and level of TNF alpha produced. In contrast, lymphotoxin (LT) and Interferon gamma (IFN gamma) (greater than 50 pg/ml) were not found. This was further investigated in the RA cultures at both the mRNA and protein level. The results indicated that high levels of mRNA were produced spontaneously by these cells, but the relevant protein was undetectable. The presence of inhibitors and/or shed receptor is unlikely to account for undetectable LT as most of the recombinant LT added to the cultures could be recovered. In addition, in some cases this resulted in an increase in IL-1 production indicating that LT is biologically active in this system. It is not clear at this stage why the protein for these mediators (produced by activated T cells) are not found in the rheumatoid cultures, although it may be due to a post-transcriptional mechanism. This possibility is currently being investigated in addition to the development of more sensitive assays for these cytokines.

Arthritis, Rheumatoid↗

PubMed1989

'Fetal-type' B and T lymphocytes in rheumatoid arthritis and primary Sjögren's syndrome.

B lymphocytes expressing CD5 (CD5+B cells) and T lymphocytes using the gamma and delta chains to form their antigen receptor (gamma delta +T cells) are major populations in developing fetuses, but become relatively minor in normal adults. However, both subsets are expanded in the peripheral blood of more than 50% of patients with rheumatoid arthritis and primary Sjögren's syndrome. We have examined the surface phenotype of these subsets using flow cytometry and have studied the frequency of IgM-producing lines after EBV-transformation of sorted CD5+B and CD5-B cells isolated from neonatal umbilical vein and RA peripheral blood. The intensity of CD5 expression on B cells was at least 10 times 'duller' than on T cells, CD5 'dull' cells were CD3 negative, and T cells bearing the gamma delta antigen receptor did not express either CD4 or CD8 on their surface. In vitro stimulation by Staphylococcus aureus Cowan I or transformation by Epstein-Barr virus of CD5+B cells resulted in loss of CD5 antigen from the surface of B cells. EBV-transformation of sorted CD5+B and CD5-B lymphocytes from neonatal blood gave rise to IgM-secretion in 100% of the Ig-secreting lines. CD5+B fraction isolated from RA blood also generated 100% IgM-secreting lines, whereas 29% of the Ig-secreting lines obtained from RA CD5-B fraction did not secrete IgM. The function of these 'fetal-type' T and B lymphocytes is unknown, however their expansion in rheumatoid arthritis and primary Sjögren's Syndrome suggests that they may play a role in autoimmune diseases.

Antigens, Differentiation↗

PubMed1989

Production of TGF-alpha and TGF-beta by cultured keratinocytes, skin and oral squamous cell carcinomas--potential autocrine regulation of normal and malignant epithelial cell proliferation.

Transforming growth factors have a wide range of biological activities related to cell proliferation and differentiation. In general TGF-alpha promotes cell proliferation while TGF-beta may stimulate or inhibit proliferation depending on the cell type and growth factor environment. Cultured human keratinocytes, skin and oral squamous cell carcinomas were analysed for the presence of transcripts and protein for the transforming growth factors alpha & beta. Both growth factors were detected in cultured keratinocytes (which have receptors for and respond to both ligands), and in medium conditioned by these cells. Additionally transcripts for TGF-alpha were found preferentially in the basal, proliferative compartment of cultured keratinocytes. Similarly both growth factors were detected in oral squamous cell carcinomas and a highly significant inverse correlation was found between the levels of TGF-alpha and the epidermal growth factor receptor in these tumours. The data for TGF-alpha are consistent with the existence of an autocrine growth control loop influencing cell proliferation in both a normal cell type and malignant epithelial tissues, a process that in keratinocytes and responsive squamous cell carcinomas could be modulated by TGF-beta.

Carcinoma, Squamous Cell↗

PubMed1989

Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune disease characterized by T-cell infiltration of the synovium of joints. Analysis of the phenotype and antigen specificity of the infiltrating cells may thus provide insight into the pathogenesis of rheumatoid arthritis. T cells were cloned with interleukin 2, a procedure that selects for in vivo-activated cells. All clones had the CD4 CDW29 phenotype. Their antigen specificity was tested by using a panel of candidate joint autoantigens. Four of 17 reacted against autologous blood mononuclear cells. Two clones proliferated in response to collagen type II. After 21 months, another set of clones was derived from synovial tissue of the same joint. One of eight clones tested showed a strong proliferative response against collagen type II. The uncloned synovial T cells of a third operation from another joint also responded to collagen type II. The persistence of collagen type II-specific T cells in active rheumatoid joints over a period of 3 years suggests that collagen type II could be one of the autoantigens involved in perpetuating the inflammatory process in rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed1989

Definition of a population of CD4-8- T cells that express the alpha beta T-cell receptor and respond to interleukins 2, 3, and 4.

Whereas most T cells express surface CD4 or CD8 molecules, a minority lacks both. CD4-8- cells usually express the gamma delta T-cell receptor, but here we describe a population of CD4-8- T cells from the peripheral blood that express the alpha beta heterodimer. These cells have different surface antigens than gamma delta+ T cells, expressing CD5 but lacking CD16, and differ in function from gamma delta+ T cells. CD4-8- alpha beta+ cells lack non-major histocompatibility complex-restricted cytolytic function but can be induced to lyse their target cells after activation of their T-cell receptors. A peculiar characteristic of these cells is their responsiveness to interleukin 3. Since these cells have not altered their phenotype or function over a 12-month period in culture, they appear to be mature T cells. The results indicate that normal human peripheral blood contains two subsets of CD4-8- T cells, expressing either gamma delta or alpha beta receptors, that differ in function, phenotype, and growth control.

Antigens, CD↗

PubMed1989

T cells and lymphokines.

T lymphocytes are one of the richest sources of protein mediators. Many of their effects, such as T cell help, growth stimulation, macrophage activation or suppression are caused by the release of these molecular mediators, which include the interleukins IL-2, IL-3, IL-4, IL-5, IL-6, interferons alpha and beta (IFN alpha and beta), tumour necrosis factor (TNF), lymphotoxin (LT), granulocyte macrophage colony stimulating factor (GM-CSF) and transforming growth factor beta (TGF beta). These molecules are only produced transiently after activation of the cells, and the CD4 (cluster differentiation antigen 4) cells are the richest sources of cytokines.

Animals↗

PubMed1989

High rate of HLA class II mRNA synthesis in rheumatoid arthritis joints and its persistence in culture: down-regulation by recombinant interleukin 2.

The expression of HLA class II mRNA was investigated in the joints of patients with active rheumatoid arthritis (RA) in order to evaluate patterns of synthesis. Northern hybridization analysis showed that HLA class II gene transcripts in RA joints were of the correct sizes, and subsequent analyses were performed by slot blotting. All active RA samples expressed high levels of HLA-DR, DP, and DQ mRNA with DP and DQ less than DR. Synovial fluid or membrane cells, chiefly a mixture of T cells and macrophages, were placed in culture, in the absence of any stimulation. The levels of mRNA remained at a high level in vitro. The half of HLA-DR mRNA in joint cells was very brief (approximately 30 min), indicating that prolonged synthesis was due to restimulation of the cells. The effect of lymphokines on HLA class II regulation on joint cell was assessed. Gamma interferon was capable of augmenting HLA-DR to some extent, but paradoxically interleukin 2 at concentrations optimal for stimulating T cells, diminished HLA-DR expression.

Adult↗

PubMed1989

3M dwarfism: a study of two further sibs.

Two sibs are reported with clinical and radiological features of the 3M syndrome. The differential diagnosis is discussed, particularly with regard to Russell-Silver syndrome.

Consanguinity↗

PubMed1989

Tumour necrosis factor synergises with gamma interferon on the induction of mRNA for DR alpha chain on thyrocytes from Graves' disease and non toxic goitre.

In both thyroid autoimmune diseases Graves' and Hashimoto's thyroiditis, the epithelial thyroid follicular cells (TFC) have been shown to express HLA class II molecules, and can restimulate autoreactive T cells cloned from the diseased tissue. This aberrant class II expression is important in the mechanism of perpetuation of the disease process, therefore we have compared the effect of interferon gamma (IFN gamma) and tumour necrosis factor (TNF alpha) on the HLA-DR alpha mRNA expression of thyroid follicular cells derived from Graves' disease (GD) and a non autoimmune disease, non toxic goitre (NTG). Our results indicate that TNF alpha synergises with IFN gamma in the induction of HLA class II mRNA. There was no consistent difference in DR alpha mRNA expression between the GD and NTG thyroid follicular cell preparations in response to induction by a combination of these lymphokines at various concentrations. Our data suggest that the differences in the level of expression of class II molecules observed in vivo in Graves' disease and non toxic goitre, which is much higher in the former, is probably due to local release of lymphokines by infiltrating T lymphocytes, although other factors may be involved.

Drug Synergism↗

PubMed1989

Coordinate expansion of 'fetal type' lymphocytes (TCR gamma delta+T and CD5+B) in rheumatoid arthritis and primary Sjögren's syndrome.

In the blood of 10 patients with rheumatoid arthritis (RA), the number of TCR gamma delta+T cells and CD5+B cells was 5.5% +/- 4.38 and 34.3% +/- 20.62 (mean +/- s.d.), respectively. In 12 patients with primary Sjögren's syndrome (SS) the mean +/- s.d. of these T and B cell subpopulations was 4.75% +/- 3.85 and 38.75% +/- 22.68. These values were significantly increased as compared with the circulating T and B cells from 22 healthy subjects in whom TCR gamma delta+T cells were 2.09 +/- 1.01 (P less than 0.001 for RA; P less than 0.004 for SS) and CD5+B cells were 18.09% +/- 4.47 (P less than 0.001 for RA and SS). This increase was not influenced by disease activity. Furthermore, there was a marked correlation (P less than 0.001) between the levels of TCR gamma delta +T cells and CD5+B cells. This novel finding of coordinate elevated levels of lymphocytes with fetal phenotypes in RA and primary SS suggests an immunological imbalance that may have implications in these diseases.

Antigens, Differentiation↗

PubMed1989

Effect of cytokines on HLA-DR and IL-1 production by a monocytic tumour, THP-1.

The monocytic tumour, THP-1, expresses many of the properties of monocytes, both by cell surface staining and its capacity to produce monokines. It was used as a source of homogenous monocytic cells as a model to determine whether a variety of highly purified or recombinant cytokines could induce HLA-DR expression and the production of interleukin-1 (IL-1). Interferon-gamma (IFN-gamma) alone induced HLA-DR. Tumour necrosis factor (TNF), lymphotoxin (LT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alone were able to induce IL-1 but not HLA-DR. When IFN-gamma was combined with TNF, induction of HLA-DR and IL-1 was enhanced in a synergistic manner. These effects were detectable at a pretranslational level as synergistic effects were observed on DR alpha mRNA and IL-1 beta mRNA levels. The results demonstrate the specificity of IFN-gamma as the inductive stimulus for HLA-DR expression by THP-1 cells. As IFN-gamma and TNF are products of activated T cells, the synergistic role for these molecules in macrophage activation is discussed.

Biological Factors↗

PubMed1989

Analysis of intrathyroidal cytokine production in thyroid autoimmune disease: thyroid follicular cells produce interleukin-1 alpha and interleukin-6.

Cytokine production was studied in thyroid tissue from patients with Graves' disease, Hashimoto's thyroiditis and non-toxic goitre. The expression of interferon gamma, tumour necrosis factor alpha and beta, interleukin-1 alpha and beta, interleukin-6 and platelet-derived growth factor A chain was assessed by slot-blot analysis of the respective mRNA in freshly isolated tissue samples. All seven cytokines were detected in patients of all groups. Although the respective mRNA levels were, in general, higher in thyroid autoimmune disorders, this appeared to relate to the degree of the lymphocytic infiltration of the thyroid gland at the time of surgery. Purified thyroid follicular cells expressed high levels of interleukin-1 alpha and interleukin-6 mRNA and when established in primary culture, purified thyroid follicular cells from Graves' disease as well as non-toxic goitre produced interleukin-1 alpha and interleukin-6 bioactivity spontaneously. In the case of interleukin-1 this could be further augmented by addition of lipopolysaccharide to the thyroid follicular cell cultures. These results demonstrate that the lymphocytic infiltrate found in autoimmune and non-autoimmune thyroid disorders is associated with cytokine production. Additionally we have shown that intrathyroidal cytokine production is not restricted to thyroid-infiltrating mononuclear cells, but may also involve thyroid follicular cells both in vivo and in vitro. The cytokines produced by thyroid follicular cells may have an important role in stimulating autoantigen specific T cells in vivo as both interleukin-1 and interleukin-6 facilitate T cell activation.

Adult↗

PubMed1989

Molecular mechanisms involved in human autoimmune diseases: relevance of chronic antigen presentation. Class II expression and cytokine production.

The observation that the local site of autoimmune responses over-expressed HLA class II led to the formulation that tissue antigen-presenting capacity contributes significantly to the mechanism of autoimmune disease perpetuation, by continually reactivating auto-antigen-reactive T lymphocytes. These in turn produce mediator molecules which maintain HLA class II expression (and hence antigen-presenting capacity) in the target tissues; and also initiate the immune and inflammatory pathways. The importance of this concept is that it provides a readily testable hypothesis that has been investigated extensively. For the thyroid diseases compelling data to support it have accumulated; in other diseases such as rheumatoid arthritis the evidence is increasing. The concept also relates the human autoimmune diseases to the normal mechanisms of immune induction and immunoregulation. This highlights the areas that we do not yet understand, namely the interplay of genetic susceptibility, extrinsic agents or disorders of immune regulation which permit the autoimmune process to become sufficiently pronounced as to engender a clinical autoimmune disease. Even with our limited understanding of the disease process, it is apparent that there are many opportunities for newer approaches at therapy, based on interfering with the immune cells or their mediators.

Antigen-Presenting Cells↗

PubMed1988

Post-transcriptional control of IL-1 gene expression in the acute monocytic leukemia line THP-1.

The acute monocytic leukemia cell line THP-1 secretes predominantly IL-1 beta after treatment with bacterial lipopolysaccharide and tumour promoting phorbol ester (PMA). IL-1 alpha is also secreted, but represents less than 10% of the total IL-1 activity. This differential is reflected at the level of mRNA as IL-1 beta mRNA is more abundant than IL-1 alpha mRNA. Studies of transcription in isolated nuclei however indicate that each gene is transcribed at a similar rate, suggesting that post-transcriptional mechanisms regulate the relative abundance of IL-1 alpha and IL-1 beta mRNA. Measurement of RNA half life after addition of alpha-amanitin (an inhibitor of RNA polymerase II) indicate that IL-1 alpha mRNA is not as stable as IL-1 beta mRNA suggesting one mechanism for the different relative levels of RNA.

Amanitins↗

PubMed1988

Do CD4-positive cytotoxic T cells damage islet beta cells in type 1 diabetes?

The mechanism by which islet beta cells are destroyed in type 1 diabetes is still unknown. Because in diabetes the majority of T cells activated in vivo express CD4 and the islet beta cells selectively express the HLA class II antigens needed for recognition by CD4-positive T cells, the possibility that selective damage to islet beta cells may be caused by CD4-positive cytotoxic cells was investigated. Activated T cells were cloned from a newly diagnosed diabetic patient, and many CD4 cytotoxic clones were detected. The clone with the highest cytolytic capacity lysed HLA class II compatible islet cells which had been induced by interferon gamma and tumour necrosis factor to express class II antigens. The specificity of the lysis was demonstrated by use of histoincompatible islets, other histocompatible target cells, and blocking by anti-class-II monoclonal antibodies. The results show that a CD4-positive T cell clone can lyse HLA class II matched islet cells; this process may be important in the pathogenesis of type 1 diabetes.

Adult↗