Early pregnancy factor treatment suppresses the inflammatory response and adhesion molecule expression in the spinal cord of SJL/J mice with experimental autoimmune encephalomyelitis and the delayed-type hypersensitivity reaction to trinitrochlorobenzene in normal BALB/c mice

Early pregnancy factor (EPF) is a secreted protein, present in serum during early pregnancy and essential for maintaining viability of the embryo. It is a homologue of chaperonin 10 (Cpn10) but, unlike Cpn10, it has an extracellular role. EPF has immunosuppressive and growth regulatory properties. Previously we have reported the preparation of recombinant EPF (rEPF) and shown that treatment with rEPF will suppress clinical signs of MBP-EAE in Lewis rats and PLP-EAE in SJL/J mice. In the present study, these findings have been extended to investigate possible mechanisms involved in the action of EPF. Following treatment of mice with rEPF from the day of inoculation, there were fewer infiltrating CD3+ and CD4+ cells in the parenchyma of the spinal cord during the onset of disease and after the initial episode, compared with mice treated with vehicle. Expression of the integrins LFA-1, VLA-4 and Mac-1 and of members of the immunoglobulin superfamily of adhesion molecules ICAM-1 and VCAM-1 was suppressed in the central nervous system (CNS) following rEPF treatment. The expression of PECAM-1 was not affected. To determine if rEPF suppressed T cell activation in the periphery, the delayed-type hypersensitivity (DTH) reaction of normal BALB/c mice to trinitrochlorobenzene (TNCB) following treatment with rEPF was studied. The results showed that treatment with rEPF suppressed the DTH reaction, demonstrating the ability of EPF to downregulate the cell-mediated immune response. These results indicate that suppression of immunological mechanisms by rEPF plays a major role in the reduction of clinical signs of disease in experimental autoimmune encephalomyelitis (EAE). (C) 2003 Elsevier Science B.V. All rights reserved.

Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10

Antigen-specific suppression of a previously primed immune response is a major challenge for immunotherapy of autoimmune disease. ReIB activation is required for myeloid DC differentiation. Here, we show that antigen-exposed DCs in which ReIB function is inhibited lack cell surface CD40, prevent priming of immunity, and suppress previously primed immune responses. DCs generated from CD40-deficient mice similarly confer suppression. Regulatory CD4(+) T cells induced by the DCs transfer antigen-specific Infectious tolerance to primed recipients in an interleukin10-dependent fashion. Thus CD40, regulated by ReIB activity, determines the consequences of antigen presentation by myeloid DCs. These observations have significance for autoimmune immunotherapy and suggest a mechanism by which peripheral tolerance might be constitutively maintained by RelB(-) CD40(-) DCs.

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

Priming to Ag can inhibit subsequent induction of an immune response to a new epitope incorporated into that Ag, a phenomenon referred to as original antigenic sin. In this study, we show that prior immunity to a virus capsid can inhibit subsequent induction of the IFN-gamma effector T cell response to a novel CD8-restricted antigenic epitope associated with the virus capsid. Inhibition does not involve Ab to the virus capsid, as it is observed in animals lacking B cells. CD8-restricted virus-specific T cell responses are not required, as printing to virus without CTL induction is associated with inhibition. However, IL-10(-/-) mice, in contrast to IL-10(+/+) mice, generate CD8 T cell and Ab responses to novel epitopes incorporated into a virus capsid, even when priming to the capsid has resulted in high titer Ab to the capsid. Furthermore, capsid-primed mice, unable to mount a response to a novel epitope in the capsid protein, are nevertheless able to respond to the same novel epitope delivered independently of the capsid. Thus, inhibition of responsiveness to a novel epitope in a virus-primed animal is a consequence of secretion of IL-10 in response to presented Ag, which inhibits local generation of new CD8 IFN-gamma-secreting effector T cells. Induction of virus- or tumor Ag-specific CD8 effector T cells in the partially Ag-primed host may thus be facilitated by local neutralization of IL-10.

Site-directed mutagenesis of the ATM promoter: Consequences for response to proliferation and ionizing radiation

Although ATM, the protein defective in ataxia-telangiectasia (A-T), is activated primarily by radiation, there is also evidence that expression of the protein can be regulated by both radiation and growth factors. Computer analysis of the ATM promoter proximal 700-bp sequence reveals a number of potentially important cis-regulatory sequences. Using nucleotide substitutions to delete putative functional elements in the promoter of ATM, we examined the importance of some of these sites for both the basal and the radiation-induced activity of the promoter. In lymphoblastoid cells, most of the mutations in transcription factor consensus sequences [Sp1(1), Sp1(2), Cre, Ets, Xre, gammaIre(2), a modified AP1 site (Fse), and GCF] reduced basal activity to various extents, whereas others [gammaIre(1), NF1, Myb] left basal activity unaffected. In human skin fibroblasts, results were generally the same, but the basal activity varied up to 8-fold in these and other cell lines. Radiation activated the promoter approximately 2.5-fold in serum-starved lymphoblastoid cells, reaching a maximum by 3 hr, and all mutated elements equally blocked this activation. Reduction in Sp1 and AP1 DNA binding activity by serum starvation was rapidly reversed by exposure of cells to radiation. This reduction was not evident in A-T cells, and the response to radiation was less marked. Data provided for interaction between ATM and Sp1 by protein binding and co-immunoprecipitation could explain the altered regulation of Sp1 in A-T cells. The data described here provide additional evidence that basal and radiation-induced regulation of the ATM promoter is under multifactorial control. (C) 2003 Wiley-Liss, Inc.

CD40 and dendritic cell function

CD40 has emerged as a key signaling pathway for the function of B cells, monocytes, and dendritic cells (DC) in the immune system, and plays a major role in inflammatory pathways of nonhemopoletic cells. CD40 is expressed by monocytes and DC and is up-regulated when DC migrate from the periphery to draining lymph nodes (DLN) in response to microbial challenge. CD154 signaling by MHC-restricted, activated CD4* T cells induces differentiation of DC, as defined by an increased surface expression of MHC, costimulatory, and adhesion molecules. Thus, CD40 functions in the adaptive immune response as a trigger for the expression of costimulatory molecules for efficient T-cell activation. CD40 ligation of DC also has the capacity to induce high levels of the cytokine IL-12, which polarizes CD4(+) T cells toward a T helper 1 (Th1) type, enhances proliferation of CD8(+) T cells, and activates NK cells. CD40 may also play an important role in the decision between tolerance and immunity and the generation of regulatory CD4(+) T cells that are thought to maintain peripheral self-tolerance in vivo.

Is maximizing resilience compatible with established ecological goal functions?

Cropp and Gabric [Ecosystem adaptation: do ecosystems maximise resilience? Ecology. In press] used a simple phytoplanktonzooplankton-nutrient model and a genetic algorithm to determine the parameter values that would maximize the value of certain goal functions. These goal functions were to maximize biomass, maximize flux, maximize flux to biomass ratio, and maximize resilience. It was found that maximizing goal functions maximized resilience. The objective of this study was to investigate whether the Cropp and Gabric [Ecosystem adaptation: do ecosystems maximise resilience? Ecology. In press] result was indicative of a general ecosystem principle, or peculiar to the model and parameter ranges used. This study successfully replicated the Cropp and Gabric [Ecosystem adaptation: do ecosystems maximise resilience? Ecology. In press] experiment for a number of different model types, however, a different interpretation of the results is made. A new metric, concordance, was devised to describe the agreement between goal functions. It was found that resilience has the highest concordance of all goal functions trialled. for most model types. This implies that resilience offers a compromise between the established ecological goal functions. The parameter value range used is found to affect the parameter versus goal function relationships. Local maxima and minima affected the relationship between parameters and goal functions, and between goal functions. (C) 2003 Elsevier B.V. All rights reserved.

Unsaturated diffusivity functions for concrete derived from NMR images

Deterioration of concrete or reinforcing steel through excessive contaminant concentration is often the result of repeated wetting and drying cycles. At each cycle, the absorption of water carries new contaminants into the unsaturated concrete. Nuclear Magnetic Resonance (NMR) is used with large concrete samples to observe the shape of the wetting profile during a simple one-dimensional wetting process. The absorption of water by dry concrete is modelled by a nonlinear diffusion equation with the unsaturated hydraulic diffusivity being a strongly nonlinear function of the moisture content. Exponential and power functions are used for the hydraulic diffusivity and corresponding solutions of the diffusion equation adequately predict the shape of the experimental wetting profile. The shape parameters, describing the wetting profile, vary little between different blends and are relatively insensitive to subsequent re-wetting experiments allowing universal parameters to be suggested for these concretes.

Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine

OBJECTIVES We sought to use quantitative markers of the regional left ventricular (LV) response to stress to infer whether diabetic cardiomyopathy is associated with ischemia. BACKGROUND Diabetic cardiomyopathy has been identified in clinical and experimental studies, but its cause remains unclear. METHODS We studied 41 diabetic patients with normal resting LV function and a normal dobutamine echo and 41 control subjects with a low probability of coronary disease. Peak myocardial systolic velocity (Sm) and early diastolic velocity (Em) in each segment were averaged, and mean Sm and Em were compared between diabetic patients and controls and among different stages of dobutamine stress. RESULTS Both Sm and Em progressively increased from rest to peak dobutamine stress. In the diabetic group, Sm was significantly lower than in control subjects at baseline (4.2 +/- 0.9 cm/s vs. 4.7 +/- 0.9 cm/s, p = 0.012). However, Sin at a low dose (6.0 +/- 1.3), before peak (8.4 +/- 1.8), and at peak stress (8.9 +/- 1.8) in diabetic patients was not significantly different from that of controls (6.3 +/- 1.4, 8.9 +/- 1.6, and 9.6 +/- 2.1 cm/s, respectively). The Em (cm/s) in the diabetic group (rest: 4.2 +/- 1.2; low dose: 5.0 +/- 1.4; pre-peak: 5.3 +/- 1.1; peak: 5.9 +/- 1.5) was significantly lower than that of controls (rest: 5.8 +/- 1.5; low dose: 6.6 +/- 1.5; pre-peak: 6.9 +/- 1.3; peak: 7.3 +/- 1.7; all p < 0.001). However, the absolute and relative increases in Sm or Em from rest to peak stress were similar in diabetic and control groups. CONCLUSIONS Subtle LV dysfunction is present in diabetic patients without overt cardiac disease. The normal response to stress suggests that ischemia due to small-vessel disease may not be important in early diabetic heart muscle disease. (C) 2003 by the American College of Cardiology Foundation.

Plasma zinc and immune markers in runners in response to a moderate increase in training volume

Changes in plasma zinc concentration and markers of immune function were examined in a group of 10 male runners (n = 10) following a moderate increase in training over four weeks. Seven sedentary males acted as controls. Fasting blood samples were taken at rest, before (T0) and after T4) four weeks of increased (+ 16 %) training and after two weeks of reduced (- 31 %) training (W. Blood was analysed for plasma zinc concentration, differential leucocyte counts, lymphocyte subpopulations and lymphocyte proliferation using incorporation of H-3-thymidine. The runners increased their training volume by 16 % over the four weeks. When compared with the nonathletes, the runners had lower concentrations of plasma zinc (p = 0.012), CD3(+) (p = 0.042) and CD19(+) lymphocytes (p = 0.010) over the four weeks. Lymphocyte proliferation in response to Concanavalin A stimulation was greater in the runners (p = 0.0090). Plasma zinc concentration and immune markers remained constant during the study. Plasma zinc concentration correlated with total leucocyte counts in the athletes at T6 (r = -0.72, p < 0.05) and with Pokeweed mitogen stimulation in the nonathletes at T6 (r = -0.92, p < 0.05). Therefore, athletes are unlikely to benefit from zinc supplementation during periods of moderately increased training volume.

Mapping the royal road and other hierarchical functions

In this paper we present a technique for visualising hierarchical and symmetric, multimodal fitness functions that have been investigated in the evolutionary computation literature. The focus of this technique is on landscapes in moderate-dimensional, binary spaces (i.e., fitness functions defined over {0, 1}(n), for n less than or equal to 16). The visualisation approach involves an unfolding of the hyperspace into a two-dimensional graph, whose layout represents the topology of the space using a recursive relationship, and whose shading defines the shape of the cost surface defined on the space. Using this technique we present case-study explorations of three fitness functions: royal road, hierarchical-if-and-only-if (H-IFF), and hierarchically decomposable functions (HDF). The visualisation approach provides an insight into the properties of these functions, particularly with respect to the size and shape of the basins of attraction around each of the local optima.