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Biomedical subjects

C M Dayan

Publications and source records attributed to C M Dayan.

30 records · Page 2Linked to original sources
PubMed1997

An antisense oligodeoxynucleotide complementary to corticotropin-releasing hormone mRNA inhibits rat splenocyte proliferation in vitro.

Expression of neuropeptides in immune tissues has been implicated in the paracrine control of immune functions. The effects of the endogenous splenic neuropeptide corticotropin-releasing hormone (CRH) on immune cell proliferation were investigated by incubating splenocytes from adult male Wistar rats in vitro with a specific antisense oligodeoxynucleotide probe complementary to CRH mRNA. Incubation of cells with 1 microgram/ml phosphodiester antisense probe for 24 h prior to stimulation with concanavalin A (Con A) resulted in a 30-65% decrease in 3H-thymidine uptake compared to controls. In spleen cells incubated with a random base sequence (nonsense) probe the uptake of 3H-thymidine was not different to that in control cells. Incubation of cells with either antisense or nonsense phosphorothioate-protected probes resulted in variable uptake of 3H-thymidine, demonstrating that these probes, unlike the phosphodiester probes, have non-specific effects on cells. Addition of synthetic CRH to the cells incubated with the antisense phosphodiester probe partially restored the proliferative response of splenocytes to Con A. Immunoreactive (ir) CRH measured by radioimmunoassay in splenocytes incubated with the antisense probe was significantly less than ir-CRH in splenocytes incubated with the nonsense probe or without probe, indicating that the expression of splenic CRH mRNA was specifically impaired. This attenuation of the cell proliferative response following reduced expression of splenic ir-CRH provides functional evidence for the involvement of endogenously synthesised immune ir-CRH in splenocyte activation.

Animals↗
PubMed1996

Human self-reactive T cell clones expressing identical T cell receptor beta chains differ in their ability to recognize a cryptic self-epitope.

Recognition of self-antigens by T lymphocytes is a central event in autoimmunity. Understanding of the molecular interactions between T cell receptors (TCR) and self-epitopes may explain how T cells escape thymic education and initiate an autoimmune reaction. We have studied five human in vivo activated T cell clones specific for the region 535-551 of human thyroid peroxidase (TPO) established from a Graves' patient. Three clones (37, 72, and 73) expressed identical TCR beta and alpha chains rearranging V beta 1.1 and V alpha 15.1, and were considered sister clones. Clone 43 differed from clone 37 and its sisters in the J alpha region only. Clone NP-7 expressed V beta 6.5 but rearranged two in-frame TCR alpha chain, both using the V alpha 22.1 segment. Fine epitope mapping using nested peptides showed that clones using identical TCR beta chains, identical V alpha, but a different J alpha recognized distinct, nonoverlapping epitopes in the TPO 535-551 region. This finding shows that a different J alpha region alone leads to a heterogeneous pattern of recognition. This indicates that the "restricted" TCR V region usage sometimes found in autoimmune diseases may not always correspond to identical epitope recognition. To confirm that clones 37 (and its sisters) and 43 recognize different epitopes, the T cell clones were stimulated with a TPO-transfected autologous Epstein-Barr virus (EBV) cell line (TPO-EBV) that presents TPO epitopes afer endogenous processing. Only clone 37 and its sisters recognizes the TPO-EBV cell line, suggesting that the epitope recognized by clone 43 is not presented upon endogenous processing. We have shown that thyroid epithelial cells (TEC), the only cells that produce TPO, express HLA class II molecules in Graves' disease and can act as an antigen-presenting cells, presenting TPO after endogenous processing to autoantigen-reactive T cell clones. We tested, therefore, whether autologous TEC induced the same pattern of stimulation as TPO-EBV; T cell clone 37 recognizes the TEC, whereas it is stimulated poorly by the TPO loaded to autologous peripheral blood mononuclear cells (PBMC). Clone 43, which fails to recognize the TPO-EBV, also fails to recognize the TEC, but is activated by exogenous TPO presented by autologous PBMC. These results show that exogenous versus endogenous processing in vivo generates a different TPO epitope repertoire, producing a "cryptic" epitope (epitope not always available for recognition). Our findings define a route by which human self-reactive T cells may escape thymic selection and become activated in vivo, thus possibly leading to autoimmunity.

Amino Acid Sequence↗
PubMed1995

Acute respiratory distress secondary to Morgagni diaphragmatic herniation in an adult.

Diaphragmatic hernias of the Morgagni type are generally thought to be asymptomatic in adults. This traditional assumption led to a delay in diagnosing a Morgagni hernia as the cause of acute respiratory distress in a chronic schizophrenic man. While Morgagni hernias are usually considered to be long-standing, we present radiological evidence of an acutely expanding hernia. The patient's symptoms were relieved by surgical repair of the hernia. We advise caution before dismissing Morgagni hernias in adults as being long-standing and clinically insignificant.

Acute Disease↗
PubMed1995

Identification of thyroid stimulating hormone receptor-specific T cells in Graves' disease thyroid using autoantigen-transfected Epstein-Barr virus-transformed B cell lines.

The importance of thyrotropin receptor (TSHR) agonist antibodies in the manifestations of Graves' disease (GD) is recognized. There are, however, no convincing reports of TSHR-specific T cells. We have previously cloned T cells specific for thyroglobulin and thyroid peroxidase (TPO) from GD lymphoid infiltrates and used autologous EBV-transformed B cell lines (EBVL) transfected with an expression vector encoding TPO to efficiently detect TPO-specific T cells. Here we used EBVL transfected with TSHR to seek TSHR-specific T cells in the GD infiltrates, after cloning the in vivo activated T cells without antigen. 3 out of 30 clones responded vigorously and reproducibly to EBVL-TSHR, with a mean stimulation index > 7. Their release of IL-2, IL-4, and IL-10 after stimulation with soluble anti-CD3 and phorbol ester was indistinguishable from the other clones from this thyroid. However, they produced relatively little IFN gamma (median IL-4/IFN gamma ratio of 0.80) compared with the other clones (median IL-4/IFN gamma ratio 0.06). Thus, this new potent method of antigen presentation, using autoantigen-transfected EBVL, has permitted the first unequivocal identification of TSHR T cells in GD thyroid, with distinct Th0/Th2 characteristics, unlike previously cloned TPO-responsive cells which have Th1 characteristics.

Antigen Presentation↗
PubMed1993

T cells involved in human autoimmune disease are resistant to tolerance induction.

Deletion of potentially self-reactive T-cell clones during intrathymic development provides an important mechanism of preventing autoreactivity. However, some potentially damaging cells may escape this process. Recent evidence suggests that these cells may be rendered 'anergic', that is, nonresponsive to Ag, in the absence of cell death. Such a mechanism may be particularly important in maintaining tolerance to organ-specific self Ag that are not expressed in the thymus. If so, the emergence of T cells resistant to anergy induction might be expected to result in autoimmune disease. It has previously been shown that anergy can be induced in human T cells in vitro by exposure to specific target peptide or bacterial enterotoxins in the absence of Ag-presenting cells. We have recently defined the antigenic specificity of multiple T-cell clones present at the site of a human organ-specific autoimmune disease, Graves' thyroiditis (Graves disease). In the current work, thyroid-derived T cells recognizing residues 535-551 of the thyroid tissue-specific enzyme, TPO3 have been used to examine whether cells actively involved in the autoimmune process are resistant to anergy induction, as defined by anergy induction with in vitro systems. Two systems were used. First, supraimmunogenic concentrations of peptide 535-551 (up to 1 mg/ml) failed to significantly anergize these T cells in the absence of APC. In addition, the bacterial enterotoxin SED that could stimulate these T cells in the presence of APC, failed to induce anergy when APC were not present. T cells from the peripheral blood of the same individual, in contrast, were anergizable with bacterial enterotoxins, using the same protocol. These results suggest that thyroid-infiltrating autoantigen-reactive T cells are refractory to induction of anergy, and the possibility is raised that this deficiency may be of importance in the development of autoimmunity.

Amino Acid Sequence↗
PubMed1993

Determinant spreading and the dynamics of the autoimmune T-cell repertoire.

In this article the authors propose a dynamic model of autoimmunity with T-cell recruitment and selection leading to changes in the specificity of the anti-self response during the course of disease. They argue that these changes are due to alterations in self-antigen presentation that lead to the display of previously cryptic self-determinants. Mechanisms that could underlie this differential self-presentation are proposed.

Animals↗
PubMed1993

Provider power: an important lesson from the US health care market.

In the development of the recent NHS reforms, little attention appears to have been paid to the American experience with health care markets. The US experience suggests that true competition is almost impossible to achieve in health care, and that providers rather than purchasers rapidly come to dominate the market. The end result of separating purchasers from providers is to inflate rather than contain health care spending. These conclusions have important implications for the future of the NHS internal market. In addition they reveal a dilemma for consultants in hospital (provider) trusts: is their first duty to the needs of the community or to the economic survival of their institution?

Delivery of Health Care↗
PubMed1991

Autoantigen recognition by thyroid-infiltrating T cells in Graves disease.

Graves disease is a common form of human autoimmune thyroiditis. It shares many pathological features and HLA associations with other, less easily studied, organ-specific autoimmune conditions such as insulin-dependent diabetes mellitus, and hence it is also a useful model for understanding these other diseases. We have previously shown that thyroid-infiltrating T cells in Graves disease that have been recently activated in vivo specifically recognize autologous thyroid epithelial cells. However, the autoantigens involved were not defined. In this study, we have made use of antigen-independent T-cell cloning techniques to show that at least three different thyroid antigens, three different epitopes on a single antigen, and two HLA class II elements are involved in this recognition process in a single individual. This demonstrates that T cells that are present and activated at the site of a human autoimmune disease may show considerable heterogeneity in their recognition of autoantigen on the target tissue. This contrasts with the limited heterogeneity recently reported in some animal models and has potentially important implications for both our understanding of the autoimmune process in humans and the design of immunotherapies to reverse it.

Adult↗