The development of insulin-dependent diabetes mellitus in non-obese diabetic mice: the role of CD4+ and CD8+ T cells.
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Biomedical subjects
A M Varey
Publications and source records attributed to A M Varey.
Effect of cyclosporin on pancreatic events and development of diabetes in BB/Edinburgh rats.
The effect of cyclosporin administered from 30 to 100 days of age on pancreatic events and the development of insulin-dependent diabetes has been studied by serial pancreatic biopsy of individual diabetes-prone BB/Edinburgh rats. Cyclosporin completely prevented the development of diabetes up to 150 days of age and reduced the incidence to 50% of controls at 452 days of age. Islet cell surface antibodies paralleled the development of diabetes. Insulin autoantibodies were unrelated to diabetes and not affected by cyclosporin. Immunohistochemical analysis of pancreatic biopsies from untreated control diabetes-prone rats with monoclonal antibodies specific for rat MHC molecules and T- and B-lymphocyte and macrophage subsets showed that the first abnormality seen in rats that subsequently developed diabetes was hyperexpression of MHC class I molecules on vascular endothelium and islet cells. This was followed by accumulation of ED1+ macrophages at perivascular and periductal sites adjacent to noninfiltrated islets. Increased expression of MHC class II molecules on vascular endothelial cells was also noted. Most cells infiltrating the islets initially were also ED1+ macrophages, followed by increasing numbers of other activated effector cells including helper and cytotoxic-suppressor T lymphocytes and natural killer cells. Obliteration of insulin-containing cells was associated with regression of the infiltrate. Treatment with cyclosporin had no effect on pancreatic hyperexpression of MHC class I molecules but markedly inhibited accumulation of ED1+ cells at extraislet sites, the subsequent recruitment of immune effector cells, and islet infiltration. This resulted in a delay of the onset of diabetes in some rats and prevention of diabetes in others.
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Interferon-gamma induces class II MHC antigens on RINm5F cells.
The ability of recombinant interferon-gamma (rIFN-gamma) to induce major histocompatibility complex (MHC) antigen expression in the rat insulinoma cell line RINm5F was investigated. The cells were stained with monoclonal antibodies specific for rat class I and class II MHC antigens. RINm5F cells endogenously expressed class I antigens; this was enhanced by rIFN-gamma. Class II antigens could not be detected on RINm5F cells, but both I-A and I-E were induced by rIFN-gamma.
Adenoma, Islet Cell↗
Interferon-mediated enhancement of thyroid major histocompatibility complex antigen expression. A flow cytometric analysis.
Epithelial expression of class II antigens encoded by the major histocompatibility complex (MHC) has been proposed as a means by which autoimmune thyroid disease may be initiated and maintained. We studied a rat thyroid epithelial cell line (FRTL-5), which constitutively expresses class I (OX18) but not class II (OX6 or OX17) determinants to quantify in vitro MHC antigen induction using flow cytometry. Recombinant rat gamma interferon (rIFN-gamma) induced dose-dependent expression of OX6 (I-A) antigen at greater than 48 h (maximum 80-90% of cells in culture at 100 U/ml), which was abrogated by DB-1, a monoclonal antibody to rat IFN-gamma. OX17 antigen (I-E) was also induced (86%) and OX18 (class I) markedly increased under these conditions. Other thyroid-active agents including the calcium ionophore A23187, dibutyryl cyclic AMP, thyroid-stimulating autoantibodies from Graves' disease patients (LATS), and TSH, caused no I-A induction. Supernatants from spleen cells stimulated with plant lectins (concanavalin A or phytohaemagglutinin), but not lectin alone, evoked substantial class II induction, which was inhibited by DB-1. These findings suggest that IFN-gamma is the central mediator of thyroid epithelial class II expression. FRTL-5 provides a powerful model for the analysis of thyroid MHC class II dynamics and a potential means of analysing the role of epithelial class II in autoimmune pathogenesis.
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Insulin autoantibodies, islet cell surface antibodies and the development of spontaneous diabetes in the BB/Edinburgh rat.
The presence of insulin autoantibodies (IAA) and islet cell surface antibodies (ICSA) was sought in two longitudinal studies, involving BB/Edinburgh rats of high (BB/E/H, n = 157) and low (BB/E/L, n = 61) susceptibility to diabetes development. Both studies were designed to correlate pancreatic morphology with cellular and humoral immunity. In Study I, groups of eight male and eight female non-diabetic rats of the BB/E/H line were killed at 15 day intervals from 30-105 days and plasma samples were obtained by cardiac puncture. In study II, 61 BB/E/H and 41 BB/E/L rats underwent pancreatic biopsy 1-3 times from 30 days of age until onset of diabetes or 150 days, plasma samples being taken from the tail vein at biopsy. Both studies revealed a higher prevalence for ICSA than IAA in BB/E rats. Whereas a highly significant association of ICSA with diabetes development was observed in study II (chi 2 = 8.30, P less than 0.005), IAA were associated with diabetes development only weakly (P less than 0.03, Mann-Witney U-rank test). No correlation between the presence of ICSA and IAA in individual rats was observed and IAA were not significantly associated with BB/E/H in preference to BB/E/L rats, although positive IAA values were significantly elevated in the former compared with the latter (P less than 0.01). These observations support the concept that IAA form part of a background of heightened autoimmunity against which frank diabetes develops in some animals.
Aging↗
Immunological responses of the BB rat colony in Edinburgh.
Several immunological responses of the spontaneously diabetic BB rat colony in Edinburgh designated (BB/E) have been studied. The proliferative responses to Con A and LPS, ability to make IL-2 and to show NK activity have been studied using diabetic and non-diabetic BB/E rats and normal Wistar rats. Our data suggest that the diabetic animals in the BB/E colony do not have marked deficiencies in any of these parameters. Lymphopenia and depressed T-cell responses do not appear to be a prerequisite for the development of diabetes in the BB/E colony.
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Immunological defects in SJL mice.
SJL mice are shown to be defective in their ability to develop suppressor cells following stimulation with Con A, a polyclonal T-cell activator. They make a normal proliferative response to this mitogen. In addition to this suppressor T-cell defect, the SJL mouse (unlike most mouse strains) does not develop a spontaneous antibody response to bromelain-treated autologous red blood cells (BrMRBC) in vitro. Although the SJL makes a normal proliferative response to LPS, antibody-forming cells against bromelain-treated autologous red blood cells are not increased following LPS in vivo nor does it manifest an increased response to SRBC or TNP. This may signify the presence of a functional B-cell defect in these animals. DBA mice are also shown, in this report, to have small numbers of antibody-forming cells to bromelain-treated autologous red blood cells but to be capable of responding to LPS in vivo with an increase in SRBC and TNP antibody responses.
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Cyclosporine affects the function of antigen-presenting cells.
The immunosuppressant drug cyclosporine (CsA) is known to affect T-cell function. We have studied the effect of CsA on the specific proliferative response of T-cell lines to antigen. In addition to blocking IL-2 release by specifically activated T-cell lines, CsA also affected the ability of irradiated spleen cells to present preprocessed antigen to T-cell lines. Irradiated spleen cells pulsed with antigen for 2 hr were able to stimulate a proliferative response in T-cell lines. Following a 2-hr pulse with CsA, antigen presentation by these irradiated spleen cells was reduced significantly, suggesting that CsA not only affects T cells, but also affects the function of antigen-presenting cells.
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Autoreactive T-cell lines specific for mouse thyroglobulin.
Autoreactive T-cell specific for mouse thyroglobulin have been established and characterized. These Lyt 1+ T cells proliferated specifically in response to thyroglobulin presented by syngeneic irradiated spleen cells. The antigen-presenting cell requirements of these autoreactive T cells appeared to be the same as those for foreign antigen (PPD) reactive T cells. All lines tested required antigen-presenting cells compatible at the I-A subregion of the H-2 complex. Both T-cell types responded to antigen presented by peritoneal cells and splenic dendritic cells, but only gave optimal responses when whole spleen cells were used. The cross-reactivity patterns of responses to mouse, rat, pig and human thyroglobulins indicated that at least two different epitopes could be recognized by the autoreactive T cells. Furthermore, these epitopes appeared to be different from those recognized by the majority of serum autoantibodies to mouse thyroglobulin.
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I-A restricted activation by T cell lines of anti-tuberculosis activity in murine macrophages.
Tuberculosis and leprosy remain two of the world's most significant diseases. Immunity involves the activation of macrophages by lymphokines but the details are unknown because there has been no objective assay for the relevant effector function using human pathogens. We previously reported the use of tritiated-uracil uptake by surviving mycobacteria as a measure of the anti-mycobacterial effect of human monocytes. We describe here the use of a modification of this assay to measure control of the proliferation of Mycobacterium tuberculosis in murine peritoneal macrophages. A bacteriostatic effect can be induced in macrophages infected with M. tuberculosis, by adding small numbers of Ly 1 +2- T cells from in vitro lines derived from immunized mice. The phenomenon is dependent on compatibility at the I-A locus of the major histocompatibility complex (MHC) and mediated by soluble factors. Such T cells also recognise and activate macrophages infected with other mycobacterial pathogens. Thus, T cells recognising shared mycobacterial antigens are active. The findings have implications for MHC linked susceptibility to mycobacterioses and the hypothesized ability of cross-reactive environmental mycobacteria to abrogate or pre-empt the protective efficacy of subsequent BCG vaccination.
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Mitogenic effects of glycolipoprotein extract from Pseudomonas aeruginosa.
Glycolipoprotein extracted from the extracellular of slime of Pseudomonas aeruginosa has been tested for its ability to cause murine spleen cells to proliferate and differentiate. The extracted glycolipoprotein was found to be mitogenic for a subpopulation of murine B cells. It also caused an increase in the number of specific antibody forming cells in vitro. The activity of this extract was sensitive to low doses of cyclosporin A. These findings may be important in understanding the mechanism(s) of host resistance to this organism.
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The differential effect of 2-deoxyguanosine on concanavalin A-induced suppressor and cytotoxic activity.
The effect of 2-deoxyguanosine (dGuo) on the generation in vitro of nonspecific suppressor cells in murine spleen cell cultures by concanavalin A (Con A) is examined. The experiments indicate that dGuo abrogates the generation of nonspecific suppressor activity by lectin stimulation of murine spleen cells. When comparisons were made between the effect of this nucleoside on the generation of suppressor and cytotoxic cells by Con A stimulation of murine spleen cells, it was found that dGuo only affected the generation of suppressor cells. The development of lectin-stimulated cytotoxicity was not affected by dGuo. In addition it was found that dGuo does not affect the NK activity of murine spleens.
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Direct staining of mouse T lymphoblasts with fluoresceinated Vicia villosa lectin.
Fluorescein conjugated Vicia villosa (Vv) lectin was used for direct staining of the surface of viable cells of various mouse lymphocyte populations. A varying proportion of polyclonally-activated T cells expressed Vv receptor although less strongly than cells of an influenza virus-specific cytotoxic T lymphocyte (CTL) clone and blasts generated in the mixed lymphocyte reaction. Cyclosporin A (CyA) treatment markedly reduced the expression of Vv receptor following concanavalin A (Con A) stimulation by between 66% and 93% with a concurrent inhibition of blastogenesis and complete abrogation of cytolytic function. Resting mouse lymphocytes and B-cell blasts were always Vv-negative. However, non-specific suppressor factor producing non-cytotoxic T-cell lines also expressed Vv receptor as shown by the weak, but specific, surface fluorescence of EL4 and BW5147 cells stained with Vv. Vv-positive cells were not restricted to a particular Ly phenotype, Vv-positive cells being found among both Lyt 1+ and Lyt2+ MLC stimulated lymphocytes. Our data suggest that the receptor for Vv lectin cannot be regarded as an exclusive differential marker for CTL.
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Effect of cyclosporin A on the function of T cells.
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