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Biomedical subjects

I Todd

Publications and source records attributed to I Todd.

At least 19 recordsLinked to original sources
PubMed1992

Stimulation of human B cells specific for Candida albicans for monoclonal antibody production.

The stimulation and immortalisation of human peripheral blood B lymphocytes specific for Candida albicans antigen were investigated. An in vitro immunisation system was employed which involved pretreatment of mononuclear cells with L-leucyl L-leucine methyl ester which removes the suppressive effects of CD8+ T cells, NK cells and monocytes. The remaining cells, CD4+ T cells, B cells and dendritic cells, were cultured with antigen and a mixture of cytokines. A mixture of IL-2, -4 and -6 was found to be optimal for antibody production as determined by an Elispot assay. Transformation of the activated B cells by Epstein Barr virus was found to be optimal after 2 days and lines secreting anti-Candida antibodies were established. These lines could form the basis for specific monoclonal antibody production by generating hybridomas, or by a newly described technique whereby cDNA encoding antibody Fab regions is transferred into phage display libraries. The overall strategy might be generally applicable for the generation of human monoclonal antibodies to infectious agents.

Antibodies, Monoclonal↗
PubMed1990

Suppression of HLA class II expression on thyrocytes by interferon-alpha 1.

Inappropriate expression of HLA class II molecules by human thyroid epithelial cells (thyrocytes) is commonly associated with autoimmune thyroid disease. HLA class II expression can be modulated in thyrocytes in vitro by a variety of substances: in particular, it is readily induced by interferon-gamma (IFN-gamma). Here we show that recombinant IFN-alpha 1 (rIFN-alpha 1) does not induce HLA class II expression by thyrocytes, but rather it suppresses the induction of such expression by rIFN-gamma. Similar effects were observed with IFN-alpha derived from a lymphoblastoid cell line. The effect of rIFN-alpha 1 on thyrocytes differs from its effect on human monocytes, reported by others, in which it was found to enhance the expression of HLA class II. Thus, rIFN-alpha 1 appears to have a differential effect on HLA class II expression, depending on the cell type involved.

Cells, Cultured↗
PubMed1990

Epidermal growth factor and transforming growth factor-alpha suppress HLA class II induction in human thyroid epithelial cells.

Inappropriate expression of HLA class II by human thyroid epithelial cells (thyrocytes) occurs in autoimmune thyroid diseases where it may contribute to the pathogenesis. Several substances have been found to induce or up-regulate thyrocyte HLA class II expression in vitro. The present investigations show that the induction of HLA class II in human thyrocytes cultured with interferon (IFN)-gamma can be partially suppressed by exposure of the thyrocytes to epidermal growth factor (EGF): this occurs when the thyrocytes are treated with the two reagents simultaneously and also when the exposure to EGF is before or after that with IFN-gamma. Concentrations of EGF at least as low as 0.1 ng/ml show this inhibitory effect, which can be over-ridden by very high concentrations of IFN-gamma. Thyrocyte HLA class II expression stimulated by thyroid-stimulating hormone (TSH) (in the presence or absence of IFN-gamma) is also suppressed by EGF. Transforming growth factor-alpha (TGF alpha), which is structurally related to EGF and interacts with the same cell surface receptor, has a similar inhibitory activity on the induction of thyrocyte HLA class II expression. The existence of substances which can down-regulate, as well as those which can up-regulate, thyrocyte HLA class II expression raises the possibility that the occurrence of such expression in vivo may be determined by the balance between factors with opposing modulatory effects.

Cells, Cultured↗
PubMed1989

Pathogenesis of type I (insulin-dependent) diabetes: possible mechanisms of autoimmune damage.

By definition, autoimmunity is a circumvention of self-tolerance. Considering the complex network of control mechanisms which initiate and regulate immune responses to foreign agents and maintain the natural state of self-tolerance, autoimmunity may result from a weakening of this delicate equilibrium at various levels. Several hypotheses have therefore been put forward to explain the 'active' immunization process against self-constituents which are normally tolerated.

Autoantigens↗
PubMed1989

Influence of tumor necrosis factor-alpha on the modulation by interferon-gamma of HLA class II molecules in human thyroid cells and its effect on interferon-gamma binding.

Cytokines are important modulators of immunological reactions, but it has been postulated that they might act on other unrelated epithelial cells. We studied the effects of recombinant interferon-gamma (rIFN gamma) and recombinant tumor necrosis factor-alpha (rTNF alpha) on normal human thyroid cells. We found that the combination of these two cytokines enhanced HLA class II molecule expression on these cells compared with the effect of rIFN gamma alone. This was proven by both immunofluorescence as well as a more sensitive and quantitative RIA. rTNF alpha alone had no effect on HLA class II molecule induction on the same thyrocytes, suggesting a synergistic rather than an additive action in combination with rIFN gamma. The addition of 600 U/ml rTNF alpha to low dose rIFN gamma (10 U/mL) enhanced class II expression by 50%, as quantified by RIA. We also demonstrated that normal thyrocytes possess distinct receptors for the two cytokines and that rTNF alpha probably augments IFN gamma binding, since it increased when the cells were first incubated with rTNF alpha. This increased binding provides an explanation for the synergistic action of rTNF alpha in enhancing class II molecule expression by rIFN gamma. We conclude that the presence of receptors for these cytokines on human thyroid cells gives a direct demonstration of their potential biological action on cells normally not involved in the immunological circuit. The phenomenon might also explain their direct or indirect involvement in vivo, such as in influencing inappropriate HLA class II molecule expression in epithelial cells affected by autoimmunity.

Binding Sites↗
PubMed1988

An autoimmune aetiology for hypothyroidism following interferon therapy for breast cancer.

Alpha-interferon has been administered as an adjuvant treatment for women with loco-regional relapse of breast cancer. During the course of treatment 5/10 (50%) of women receiving interferon developed de novo thyroid autoantibodies. Three patients became clinically myxoedematous, with biochemical evidence of hypothyroidism which responded to thyroxine replacement therapy. The leucocyte alpha-interferon preparations used in the trial enhanced Class I but not Class II MHC antigens on thyrocytes in vitro. These data strongly suggest that patients receiving alpha-interferon therapy should be closely monitored for the possible development of thyroid dysfunction and that thyroid antibody determination can greatly help to predict overt thyroid clinical abnormalities.

Autoantibodies↗
PubMed1988

Occurrence of thyrocyte HLA class II expression in a wide variety of thyroid diseases: relationship with lymphocytic infiltration and thyroid autoantibodies.

The proteins of the major histocompatibility system (HLA in humans) play an essential role in the regulation of immune responses due to their involvement in the presentation of antigen to T lymphocytes. Thyroid follicular cells (thyrocytes) from patients with Graves' disease and Hashimoto's thyroiditis demonstrate increased expression of HLA class I and aberrantly or inappropriately express class II antigens, a phenomenon that may play an important role in the pathogenesis of these autoimmune diseases. To establish if these changes in the expression of HLA molecules are characteristic of thyroid autoimmune disease, the immunopathological features (including class I and class II antigen expression) of 100 thyroidectomy specimens from patients with nonautoimmune thyroid disease were studied by indirect immunofluorescence, and the results compared with the findings in specimens from 14 patients with Graves' disease and 12 subjects undergoing laryngectomies for carcinoma. Increased class I product expression was found in 61% of all tissues studied, with maximal occurrence in papillary carcinomas (100%) and Graves' disease (86%), but it was also detected in 50% of the glands containing nodular lesions and in 16% of the control glands. Inappropriate class II molecule expression was found in Graves' disease (71%), hyperplastic nodules (53%), multinodular glands (44%), papillary carcinomas (38%), and 16% of the control glands. In summary, an increase in inappropriate HLA class I and class II expression was very common in nonautoimmune thyroid glands, but it generally occurred in the context of lymphocytic infiltration and thyroid autoantibodies (i.e. focal thyroiditis). Multiple correlation analyses of these 4 phenomena indicated heterogeneity in the mechanism leading to the inappropriate expression of thyrocyte class II antigens in the different conditions studied.

Adolescent↗
PubMed1988

Mapping cell-glass contacts of Dictyostelium amoebae by total internal reflection aqueous fluorescence overcomes a basic ambiguity of interference reflection microscopy.

The widespread ability of eukaryotic cells to produce thin cytoplasmic sheets or lamellae 100-200 nm thick can give rise to uncertainties in the interpretation of interference reflection microscopy (IRM) images when cell-substratum topography is the key interest. If allowed to spread upon a poly-L-lysine-coated surface, Dictyostelium discoideum amoebae typically form ultrathin lamellae of approximately equal to 100 nm thickness by cytoplasmic retraction. Whereas the cell body is grey, the lamellae appear very dark under IRM optics. These dark areas could be misinterpreted as stemming from a closer cell-substratum apposition beneath the lamellae than the cell body. This ambiguity can be avoided if the technique of total internal reflection aqueous fluorescence (TIRAF) is used in conjunction with a high refractive index glass (n = 1.83) as substratum. Contributions to the image generated by thin cytoplasm and also variable cytoplasmic refractive index are thereby minimized due to the extremely short range of the 'illuminating' evanescent wave. From our comparative IRM and TIRAF study of the ultrathin lamellae of Dictyostelium amoebae it is concluded that the cell-glass gap is relatively uniform beneath the entire cell. We briefly discuss the sensitivity of several cell types to TIRAF, the generation of ultrathin lamellae and the nature of the cell-glass gap.

Cell Adhesion↗
PubMed1987

A randomized trial of two types of adjuvant chemotherapy in radiotherapy-treated patients with clinical stages I and II high-grade non-Hodgkin's lymphoma.

This paper reports the 8-year results of comparing the use of two types of adjuvant chemotherapy following involved field radiotherapy for clinical stages I and II high-grade non-Hodgkin's lymphoma. Twenty-four patients received 6 weeks of VAP plus 2 years of oral maintenance chemotherapy, and 30 had six cycles of CMOPP. Four patients were not in complete remission at completion of i.v. chemotherapy (CR rate 91%). Ten patients (18.5%) have relapsed (VAP/M = 5; CMOPP = 5), with only two of these remaining alive, both of them being disease free. There have been three deaths from intercurrent causes, one from malignant melanoma and the other two from myocardial infarction. The relapse-free survivals at 2, 5 and 8 years were 80%, 76% & 76% respectively. The overall survivals at the same time points were 86%, 72% & 68%. There were no significant differences in either relapse-free or overall survival for either of the two treatment groups. The shorter period of weekly intravenous chemotherapy (VAP/M) was better tolerated than 36 weeks of CMOPP, and the former appears to produce equivalent results.

Adolescent↗
PubMed1987

New ideas in thyroid autoimmunity.

Endocrine epithelial cells do not normally express human leukocyte antigen (HLA) class II molecules, but do so in a variety of autoimmune diseases. This finding suggests the hypothesis that such inappropriate class II-positive expression may enable these cells to present autoantigens and thus contribute to autoimmune pathogenesis. Indeed, class II-positive thyrocytes can present both exogenous antigenic peptides and intrinsic autoantigens to the appropriate T cells. Class II expression by thyrocytes can be induced by interferon-gamma, and is positively and negatively regulated by thyroid-stimulating hormone and epidermal growth factor, respectively. Furthermore, heterogeneity of thyrocyte class II subregion expression appears to be related to the nature of the inducing stimulus. The complexity of regulatory signals is underlined by findings in type I diabetes: islet beta cells aberrantly express class II in this disease, but class II cannot be induced in normal beta cells by interferon-gamma.

Antigen-Presenting Cells↗
PubMed1987

Thyrocyte HLA class II expression and regulation in relation to thyroid autoimmunity.

The occurrence of HLA Class II expression by thyroid (and other endocrine) epithelia in autoimmune diseases suggests that these cells may facilitate their own destruction by immunogenically presenting autoantigens. This is supported by the findings that Class II+ thyrocytes can specifically stimulate virus-specific and autoreactive T cell clones, and that Class II expression by thyrocytes correlates with the occurrence of thyroid autoantibodies. A variety of factors may contribute to the regulation of Class II expression by thyrocytes: this is induced by interferon (IFN-gamma), and is enhanced by thyroid stimulating hormone (TSH) and by tumour necrosis factor (TNF). Conversely, epidermal growth factor (EGF) suppresses the induction of Class II in thyrocytes. This complex regulation is reflected in differences in HLA-D subregion expression between patients (DR greater than DP greater than DQ). The immune-based mechanisms of thyrocyte Class II regulation are clearly applicable to the on-going disease in an infiltrated thyroid, but the possibility of nonimmune Class II induction deserves attention, particularly in identifying factors which might contribute to the initial autoimmune attack. The possible involvement of such mechanisms in autoimmunity is supported by findings in Type I diabetes in which Class II+ islet beta cells can be found in the absence of infiltration. Further evidence is provided by the observation that a proportion of thyrocytes transformed with SV40 DNA constitutively express Class II molecules. Finally, the 'activated' state of capillary endothelial cells in organs subject to autoimmune attack suggests that they may play an important role in facilitating the autoreactive infiltration of the tissues.

Epithelium↗
PubMed1987

Enhancement of thyrocyte HLA class II expression by thyroid stimulating hormone.

HLA Class II molecules are expressed by human thyroid epithelial cells (thyrocytes) in thyroid autoimmunity, although these cells are normally Class II-. gamma-Interferon (gamma-IFN) is probably involved in this expression, as suggested by its ability to induce Class II in cultured normal thyrocytes. We have now found that thyroid stimulating hormone (TSH) enhances Class II expression induced in cultured thyrocytes by gamma-IFN, and effects similar to those of TSH were obtained with dibutyryl cyclic AMP. A proportion of thyrocytes also expressed Class II following treatment with TSH or dibutyryl cyclic AMP in the absence of gamma-IFN, but the optimal activity of these mediators then appeared to be dependent upon the occurrence of some pre-existing Class II expression. These findings give insights into how a variety of mediators may influence Class II expression in thyroid autoimmunity.

Autoimmune Diseases↗
PubMed1987

HLA-D subregion expression by thyroid epithelium in autoimmune thyroid diseases and induced in vitro.

Human thyroid epithelial cells (thyrocytes) express HLA Class II molecules in autoimmune thyroid diseases (ATD). Normal thyrocytes do not express Class II, but can be induced to do so by culture with interferon-gamma (gamma-IFN). We have examined HLA-D subregion expression in sections and monolayers of thyroid by indirect immunofluorescence using appropriate monoclonal antibodies. The results indicate that, in ATD, the incidence and intensity of Class II subregion expression by thyrocytes varies between patients, and follows the pattern DR greater than DP greater than DQ. The same hierarchy is observed in cultured normal thyrocytes treated with gamma-IFN: strong induction of Class II, and of DP and DQ in particular, requires relatively high concentrations of gamma-IFN or additional factors such as thyroid stimulating hormone. These findings suggest that HLA-D subregion expression by thyrocytes in on-going ATD is determined by the levels of disease related factors in the affected tissue.

Autoimmune Diseases↗