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Legume grains such as field peas and field beans can be produced on a local level, and may be reliable sources of dietary protein and energy apart from common soybean and rapeseed meals. In ruminants, protein, starch, and carbohydrates from peas and field beans are fermented in large part before reaching the small intestine. The objective of this study was to evaluate the effects of a combination of ensiling and hydro-thermic treatment (i.e., toasting at 160 °C for 30 min) of grains of peas and field beans on the concentrations of post-ruminal crude protein (PRCP) and rumen-undegraded protein (RUP). Moreover, 24-h gas production and methane production were measured. For this, an in vitro batch culture system with ruminal fluid from sheep was used. Rumen-undegraded protein was determined using the Streptomyces griseus protease test. Scanning electron micrographs were used to visualize morphological changes of starch granules and their joint matrices in peas and field beans after ensiling, toasting, or a combination of both. Native pea grains contained crude protein (CP) at 199 g/kg DM, PRCP at 155 g/kg DM at a ruminal passage rate of 0.08/h (Kp8), RUP at 33 g/kg DM at Kp8, and starch at 530 g/kg DM. Native field beans contained CP at 296 g/kg DM, PRCP at 212 g/kg DM at Kp8, RUP at 54 g of/kg DM at Kp8, and starch at 450 g/kg DM. The PRCP did not considerably differ among native and treated peas or field beans. Especially in the peas, RUP at Kp8 increased after ensiling by 10 g/kg DM (i.e., 30%; P

Partitioning of apparent digestibility is helpful to assess the nutritive value of feedstuffs and to identify possible risks for digestive disorders. In horses, information on partial digestibility is less available and address less on carbohydrate fractions. It is suggested that large parts of water-soluble carbohydrates (WSC) are degraded already in the stomach, which elevates the risk for mucosal ulceration. Our objective was to investigate apparent digestibility of dry matter (DM), proximate nutrients, and WSC along the digestive tract using internal and external markers. Twelve adult horses were adapted for 20 d to meadow hay (1.5 kg/100 kg body weight per day) and crushed oats (1.2 g starch/kg body weight per day), which were offered 2 times a day. Six horses on the treatment group also received 0.15 g of fructooligosaccharides + inulin (via Jerusalem artichoke meal) per kg body weight per day. The other 6 horses on the control group received corncob meal without grains. The tested markers were 4 N acid insoluble ash (AIA), acid detergent lignin (ADL), n-heptacosane, n-nonacosane, n-hentriacontane, and n-tritriacontane. Additionally, Cr2O3 (approximately 2.8 g/bolus) and TiO2 (approximately 2.5 g/bolus) were provided as a bolus 2 times a day. The horses were euthanized at d 21 approximately 1 h after the morning meal. Samples of digesta were collected from the stomach (pars nonglandularis and pars glandularis), cecum, ventral and dorsal colon ascendens, and colon transversum. Feces were sampled at 5 d ante mortem. Compartmental and total tract apparent digestibility was calculated for each horse. The stomach seemed to be considerably involved in nutrient degradation with particular great disappearance of simple sugars, starch, and fructans (apparent digestibility was up to 78, 74, and 56%). No WSC were measured in the cecum. In the hindgut, apparent digestibility increased from the cecum to the colon transversum (e.g., for DM: 0.49–0.79 with AIA, and 0.44–0.56 with n-tritriacontane; for crude protein: 0.51–0.82 with AIA, and 0.47–0.63 with n-tritriacontane; and for neutral detergent fiber: 0.43–0.76 with AIA, and 0.37–0.50 with n-tritriacontane; P

Resident memory B (BRM) cells develop and persist in the lungs of influenza-infected mice and humans; however, their contribution to recall responses has not been defined. Here, we used two-photon microscopy to visualize BRM cells within the lungs of influenza -virus immune and reinfected mice. Prior to re-exposure, BRM cells were sparsely scattered throughout the tissue, displaying limited motility. Within 24 h of rechallenge, these cells increased their migratory capacity, localized to infected sites, and subsequently differentiated into plasma cells. Alveolar macrophages mediated this process, in part by inducing expression of chemokines CXCL9 and CXCL10 from infiltrating inflammatory cells. This led to the recruitment of chemokine receptor CXCR3-expressing BRM cells to infected regions and increased local antibody concentrations. Our study uncovers spatiotemporal mechanisms that regulate lung BRM cell reactivation and demonstrates their capacity to rapidly deliver antibodies in a highly localized manner to sites of viral replication.

The basis of a successful assessment of the nutritive value of feeds and an animal's supply with dietary energy and nutrients is having sufficient knowledge on key indicators such as feed intake, diet composition, digestibility and the kinetics of gut passage. In horses and other equids, the determination of such indicators is impractical outside controlled conditions, particularly in pasture-based husbandry. Natural wax components such as n-alkanes, alkenes, primary alcohols and fatty acids might be beneficial estimators, but their application is limited in practice. This review provides a concise view into the application of plant wax components, especially alkanes and their external counterparts, in equine nutrition studies. Recent methodological developments and the current state of knowledge are summarized as an interim conclusion. Methodological limitations still hamper an easy application of the method, and some perspectives for future methodological research are discussed. Conclusively, little information is available on feed plant concentrations and variations of primary alcohols, fatty acids and alkenes, and their natural carbon isotope (13C/12C) ratios. Moreover, the magnitude and the (in)consistency of faecal recovery of these markers is barely described. Methodological research should continue focusing on an effective application of plant markers. In horses, especially plant marker-based methods for the estimation of diet composition and passage kinetics will require much more consideration.

For a period of 20 days, 12 horses either received a prebiotic supplementation with fructooligosaccharides and inulin via Jerusalem artichoke meal (JAM) or corncob meal without grains (CMG) as placebo. The horses were euthanized 1 hour postprandial, gastric digesta was sampled from pars nonglandularis (PNG) and pars glandularis (PG), and concentrations of starch, mono- and disaccharides, fructans, d - and l -lactic acid, and short chain fatty acids were analyzed. Concentrations of starch and simple sugars were widely the same in JAM supplemented and not supplemented meals. However, fructans were less than half as much without supplementation as with supplementation of JAM. Glucose, fructose, sucrose, and fructans disappeared to a larger extent with prebiotic supplementation than without (106.6% vs. 86.7% glucose, 73.1% vs. 66.8% fructose, 91.5% vs. 14.7% sucrose, and 68.3% vs. 35.4% fructans remained in PNG; 81.9% vs. 38.3% glucose, 52.2% vs. 53.4% fructose, 47.1% vs. 0% sucrose, and 48.5% vs. 31.7% fructans remained in PG with CMG vs. JAM feeding). Disappearance of simple sugars and fructans was primarily associated with appearance of n-butyric acid (r = -0.21 – r = -0.33).

Virus-like particles (VLPs) have made giant strides in the field of vaccinology over the last three decades. VLPs constitute versatile tools in vaccine development due to their favourable immunological characteristics such as their size, repetitive surface geometry, ability to induce both innate and adaptive immune responses as well as being safe templates with favourable economics. Several VLP-based vaccines are commercially available including vaccines against Human Papilloma Virus (HPV) such as Cervarix®, Gardasil® & Gardasil9® and Hepatitis B Virus (HBV) including the 3rd generation Sci-B-Vac™. In addition, the first licensed malaria-VLP-based vaccine Mosquirix™ has been recently approved by the European regulators. Several other VLP-based vaccines are currently undergoing preclinical and clinical development. This review summarizes some of the major findings and recent advances in VLP-based vaccine development and technologies and outlines general principles that may be harnessed for induction of targeted immune responses.

Background: Significant hope and expectation has been placed on serological immunoassays to test for previous COVID-19 infection, to determine immunity against

Background: Serological immunoassays that are able to identify protective immunity against SARS-CoV-2 are urgently required to adapt quarantine measures, assess

Interleukin-1β (IL-1β) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1β activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1β. The vaccine hIL1bQb consisting of full-length, recombinant IL-1β coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1β-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1β-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1β and represents a new treatment option for IL-1β-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).

Synthetic alkanes can be applied as external markers to estimate faecal output, digestibility and passage kinetics and are furthermore easy to combine with plant alkanes for the estimation of feed intake. Successful application requires an accurate and uniform labelling of boluses or feedstuffs, which is in turn supported through simplified handling of the markers during preparation. In this study, it was tested whether melting of synthetic alkanes to wax is able to enhance the accuracy and uniformity of subsequent bolus labelling and further simplifies it. The preparation of alkane waxes was performed on model scale using a portion in a ratio of approximately 1:300 to a dosage, which is recommended for administration in large livestock 2 times a day. Additionally, the temperature sensitivity of a range of synthetic alkanes was studied to clarify so far non-explained losses of alkanes, which were observed frequently during the labelling of boluses and feedstuffs or the processing of samples for analysis. Using n -octacosane (C28), n -dotriacontane (C32) and n -hexatriacontane (C36) synthetic alkanes, three single-component waxes (of C28, C32 and C36, respectively), three binary waxes (C28:C32, C28:C36 and C32:C36) and one tertiary mixed wax (C28:C32:C36) were produced with 30 repetitions each. To assess the impact of melting and re-crystallization, the quantity of individual alkanes was determined by gas chromatographic analysis (GCA) in untreated crystals, crystalline mixtures (GCA1) and the finished model waxes (GCA2). Additionally, sub-samples of the waxes were heated for 30 min at 100 °C or freeze-dried for 48 h, respectively, to simulate baking of boluses or freeze-drying as an alternative method for preparation (GCA3). The temperature sensitivity of n -tetracosane (C24) to n -octatriacontane (C38) even-chain alkanes was studied by thermogravimetric analysis (TGA) with consistently increasing temperature (20 to maximal 600 °C at 10 K/min, TGA1) and under isothermal conditions (180 °C for 20 min, TGA2), respectively. Depending on chain length and thus molecular weight of alkanes, weight reduction by emergence of soot during heating-up started between 176 °C (C24) and 227 °C (C38) and further increased rapidly. Throughout isothermal treatment, weight loss from alkanes was lowest with highest chain length (0.0% for C38) and vice versa (23.8% for C24). The originally weighed and via GCA measured quantities of crystalline alkanes did not differ ( P >0.05), except for single C36, where the measured quantities were always higher than the weighed ones ( P =0.019). The weighed and measured quantities of individual alkanes in single-component and of total alkanes in multi-component waxes were similar with a maximal relative difference of 6.6±5.5%, given as the mean ± standard deviation among the repetitions of a sample variant. The relative difference between weighed and measured quantities of individual alkanes in multi-component waxes was maximal 47.4±25.7% and was highly variable. Unexpectedly, the relative difference between weighed and measured quantities was low for C28 (5.9±5.8%) and C32 (5.7±4.3%) in their combined binary waxes. The additional treatment (baking or freeze-drying) did not alter the recovery of alkanes from the model waxes. Synthetic alkanes are thermolabile why exposure to high temperature during preparation of boluses or labelling of feedstuffs needs to be assessed critically. Reasons for that might be complex disorders of the conformation of alkane molecules particularly during the melting of alkane mixtures and the apparently incomplete separation following re-crystallization from the melt. This may lead to displacements within waxes, which cannot be foreseen or quantified, and thus to the loss of their suitability as dietary markers. Alkane recovery from binary waxes of C28 and C32 was unbiased on model scale and whether this can be confirmed on original scale needs to be validated further. For practical use, alkane waxes might nevertheless be beneficial because the handling is easier than that of alkane crystals.

External markers are useful or required to estimate forage intake, digestibility, faecal output and passage rate in horses. Oral administration is challenging because of horses’ high sensitivity and selection skills. A suitable bolus matrix should ensure high and consistent acceptance. Boluses were investigated with and without labelling. Synthetic alkane wax, embedded in filter paper or contained in hypromellose capsules, was used as a test marker. Boluses were baked (100 °C, 30 min) or freeze-dried. The freeze-dried boluses varied in size (1.5, 2, or 3 cm O ) and drying time (6, 12, 24, or 48 h). In two tests (AT1 and AT2), acceptance by the horses was assessed with scores between 1 (complete intake) and 4 (refusal). In AT1, marginal rejection of the marker was recorded, whereas the following tests were performed with placebos only. In two bending tests (BT1 and BT2), the force required to break the boluses (FL, flexural load) was determined because this may affect acceptance. Pre-selected variants were stored for 4 weeks in closed boxes under controlled conditions (20 °C and light for 16 h/d, 16 °C and night for 8 h/d, and 65% relative humidity) and were subsequently analysed for residual moisture (RM) and spoilage-indicating microbes. In baked boluses, the alkanes were partly found outside of the inner matrices. This was not evident in the freeze-dried variants. Acceptance of the labelled boluses (scores≤1.7±0.18, AT1), baked placebos (scores≤2.2±0.35, AT1) and the freeze-dried placebos (scores≤1.1±0.31, AT2) was consistently high. This was explained by the BT, with a mean FL of 202±16.5 N for the baked (BT1) and up to 257±22.5 N for the freeze-dried placebos (BT2) being obtained, which was close to the masticatory forces in horses. However, when the boluses distinctly exceeded a size of 3 cm O , this size probably led to increased FL (BT1), thereby depressing the acceptance of the dried placebos (AT1). The results indicated that the adaption to suitable boluses can lead to increased acceptance. Limiting the drying time to at most 24 h seemed justified, especially for the smaller boluses. After 6 and 12 h, the RM was 7.5±0.52% (1.5 cm O ) and 5.7±0.52% (2 cm O ), which make the risk of microbial spoilage appear low. Tested boluses were unspoiled for up to 1 month after preparation. It was suggested that the variable sizes of the boluses may enable the use of various marker dosages and, incidentally, also use in different target animals. A freeze-dried matrix is likewise open to use with other thermolabile markers or substances. We recommend the pre-administration of placebos prior to marker administration to ensure high acceptance of the labelled boluses.

The bean seed beetle (Bruchus rufimanus) is the most damaging pest and responsible for significant losses of grain quality, proceeds and yield in faba bean cultivation, but cannot efficiently be opposed at present. Apart from selection of resistant cultivars, we propose earlier harvest of grains interrupting the beetles’ life cycle for improved pest control.

Fructooligosaccharides (FOS) and inulin may modulate hindgut fermentation. It was tested if digesta batch cultures taken from horses adapted to FOS and inulin show different fermentation compared with such taken from nonsupplemented horses. Six horses received 0.15 g FOS and inulin/kg body weight/d via Jerusalem artichoke meal (JAM) upon a hay-based diet; six horses received corncob meal without grains (CMG) as placebo. The horses were euthanized after 20 days. Digesta samples were taken from stomach, cecum, ventral colon ascendens (VCA), and colon transversum (CT). Digesta batch cultures were incubated 48 hours to measure in vitro gas production as well as pre- and post-incubation pH and oxidation-reduction potential (ORP). A distinct fermentation of the surplus of fructans present in the inoculum was found with JAM-adapted batch cultures. Gas production was accelerated in inoculated gastric contents of horses adapted to JAM compared with CMG adapted ones (7.8 vs. 16.4 hours to achieve half of the 48 hours gas quantity, respectively; P > .05). Although buffered, pH decreased during fermentation. Postincubation pH was lower with JAM than CMG-adapted batch cultures (P > .05). Preinoculation ORP was lower with stomach batch cultures adapted to CMG than with such adapted to JAM. The ORP increased twofold from pre- to post-incubation with the latter. Asymptotic maximal gas production decreased gradually using cecum, VCA, or CT digesta. Parts of FOS and inulin of digesta are fermented in the stomach, which reduce possible effects on hindgut fermentation. Elevated fermentation may considerably impact stomach health.

Background Type I hypersensitivity is mediated by allergen-specific IgE, which sensitizes the high-affinity IgE receptor FceRI on mast cells and basophils and drives allergic inflammation upon secondary allergen contact. CD23/FceRII, the low-affinity receptor for IgE, is constitutively expressed on B cells and has been shown to regulate immune responses. Simultaneous binding of IgE to FceRI and CD23 is blocked by reciprocal allosteric inhibition, suggesting that the 2 receptors exert distinct roles in IgE handling. Objective We aimed to study how free IgE versus precomplexed IgE-allergen immune complexes (IgE-ICs) target the 2 IgE receptors FceRI and CD23, and we investigated the functional implications of the 2 pathways. Methods We performed binding and activation assays with human cells in vitro and IgE pharmacokinetics and anaphylaxis experiments in vivo. Results We demonstrate that FceRI preferentially binds free IgE and CD23 preferentially binds IgE-ICs. We further show that those different binding properties directly translate to distinct biological functions: free IgE initiated allergic inflammation through FceRI on allergic effector cells, while IgE-ICs were noninflammatory because of reduced FceRI binding and enhanced CD23-dependent serum clearance. Conclusion We propose that IgE-ICs are noninflammatory through reduced engagement by FceRI but increased targeting of the CD23 pathway.

Background Glioblastoma (GBM) is a highly malignant brain tumour with no curative treatments. Immunotherapies, including immune checkpoint inhibitors (ICI) are under clinical evaluation, but have not yet been proven to have major impact. The low immune infiltration and modest mutational load of most GBM suggest that combination therapies will be required to improve sensitivity to immunotherapies. Methods Two mouse GBM models were used, the immunogenic GL261 and the stringent, less mutated SB28. A novel, brain-penetrant, microtubule-targeting agent, BAL101553 (BAL) which induces tumour cell death through activation of the spindle assembly checkpoint, and an agonistic anti-CD40 antibody were combined with ICI (antibodies targeting PD-1 and CTLA-4) to evaluate potential therapeutic synergy. Tumours were analyzed molecularly (mutations, transcriptional profiling) and immunologically (immune infiltration, therapy response in T/B-cell deficient mice). Results Well-tolerated combination therapies that significantly enhanced survival were identified in both SB28 and GL261 GBM models. The aggressive SB28, most representative of untreated human GBM, was most responsive to BAL combined with anti-CD40 (median survival in days: vehicle=27, anti-CD40=29, BAL=42, BAL/CD40=49); this effect was found to be T-cell independent as a similar result was observed in SB28 glioma-bearing immunodeficient (RAG1 KO) mice. The immunogenic GL261 model was, as predicted, responsive to ICI; it was relatively insensitive to BAL and anti-CD40 monotherapies but responsive to a combination of these two treatments (median survival in days: vehicle=28, anti-CD40=30, BAL=33, BAL/CD40=40). Conclusion Combination GBM therapies that include immunomodulation will likely require selection of patients according to immunological characteristics. Most clinical exploration of immunomodulators focusses on enhancing T-cell mediated anti-tumour immunity but our data suggest that synergistic combination of a tumour checkpoint controller and immunostimulation can be appropriate for poorly immunogenic GBM that is refractory to T-cell control. Legal entity responsible for the study The authors. Funding Basilea Pharmaceutica Ltd. Disclosure P. McSheehy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. F. Bachmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. H. Lane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. P.R. Walker: Advisory / Consultancy, Research grant / Funding (self): Basilea Pharmaceutica Int. Ltdtd. All other authors have declared no conflicts of interest.

To assess the practical use of pedometers as supervision tools in the equine prepartal period, two types, IceQube ® - and ALT-sensors, were tested. Nine mares were randomly fitted with devices of the respective types on the front legs (ALT: n =9, IceQube ® : n =7), and with an IceQube ® -sensor on a neck collar ( n =7). Measurements of 10 days ante partum for motion activity, lying times and lying bouts with a measuring interval of 15min were used to analyse changes during the ante partum interval. Technical function, animal acceptance, informative value, and the general use of the assessed data to predict the date of parturition, were observed and investigated, respectively. Therefore, deviations in the animals' behaviour were statistically determined by estimating least squares means (LSM), and their differences between the days ante partum and the day of parturition to the same hours, respectively ( P ante partum . In contrast, relatively constant patterns of motion within the same hours on the other days before were observed. These results were used to develop a real-time method that can detect the upcoming birth. The method is based on the actual moving average of motion activity and the 95th percentile of motion activity of the day before. For most mares, increasing moving average values above the 95th percentile were observed in the last two to one hours before parturition. The correlation for motion activity between the leg-instruments' data was calculated with r =0.51 during stable times. Lying times increased significantly ante partum , but this effect was too close to the beginning of parturition, and therefore not useable as a predictive marker. Lying time per day and per hour varied between the animals, and was generally on a very low level. The IceQube ® -sensors on the mares' neck collars recorded a permanent lying bout of these devices, which was increasingly fragmented due to movements of the head and the neck prior to parturition. This observation can be explained as colicky behaviour under pain. We suggest that this parameter could have a high predictive value. The number of lying bouts increased within the last prepartal hours, however, the analysed data of the single mares displayed again a high variability. The correlation for the recorded lying time was r =0.71 between IceQube ® - and ALT-devices at the mares' front legs. In conclusion, pedometers, regardless of which type tested, possess a high potential as supervision tools in the prepartal period of mares, especially two to one hours before birth. A prerequisite is, however, that the assessed data is analysed thoroughly with a suitable method.

A new measurement strategy is introduced to determine very pronounced crystallographic textures of polycrystalline materials most accurately and efficiently. It features optimized adaptively refined successive X-ray pole figure measurements. To optimize both the total experimental time as well as the angular resolution, and thus the accuracy of pole figure measurements, traveling salesman problems on the hemisphere of poles have to be resolved. The corresponding algorithm is encoded and implemented as part of the software controlling the texture goniometer. The procedure was applied to pole figure measurements of a NiW alloy with extremely sharp Cube texture. The results are presented and compared to conventional measurement strategies.

Summary The contribution of Toll-like receptor (TLR) signaling to T cell-dependent (TD) antibody responses was assessed by using mice lacking the TLR signaling adaptor MyD88 in individual cell types. When a soluble TLR9 ligand was used as adjuvant for a protein antigen, MyD88 was required in dendritic cells but not in B cells to enhance the TD antibody response, regardless of the inherent immunogenicity of the antigen. In contrast, a TLR9 ligand contained within a virus-like particle substantially augmented the TD germinal center IgG antibody response, and this augmentation required B cell MyD88. The ability of B cells to discriminate between antigens based on the physical form of a TLR ligand probably reflects an adaptation to facilitate strong antiviral antibody responses.

Background:Induction of allergen-specific IgG antibodies is a critical parameter for successful specific immunotherapy (SIT). IgG antibodies may inhibit IgE-mediated mast cell activation by direct allergen-neutralization or via the inhibitory receptor FcγRIIb. The affinity of IgE antibodies to the allergen has been shown to be critical for cellular activation.Objective:Here we addressed the question of the affinity thresholds of allergen-specific IgG antibodies for inhibition of mast cell activation by using 2 different monoclonal antibodies against the major cat allergen, Fel d 1, both in vitro and in vivo in mice.Methods:The sequences of the two high-affinity mAbs were back-mutated to germ-line, resulting in low affinity (10-7M) antibodies of the exact same specificity.Results:Using these newly generated recombinant antibodies, we demonstrate that low affinity antibodies are still able to inhibit mast cell activation via FcγRIIb but fail to neutralize the allergen.Conclusion:Antibody affinity dictates the mechanism of mast cell inhibition and IgG antibodies triggering the inhibitory FcγRIIb-pathway may show a broader cross-reactivity pattern than previously thought. This indicates that SIT generates a larger protective umbrella of inhibitory IgG antibodies than previously appreciated.

Pre-existing immunity against vaccine carrier proteins has been reported to inhibit the immune response against antigens conjugated to the same carrier by a process termed carrier induced epitopic suppression (CIES). Hence understanding the phenomenon of CIES is of major importance for the development of conjugate vaccines. Virus-like particles (VLPs) are a novel class of potent immunological carriers which have been successfully used to enhance the antibody response to virtually any conjugated antigen. In the present study we investigated the impact of a pre-existing VLP-specific immune response on the development of antibody responses against a conjugated model peptide after primary, secondary and tertiary immunization. Although VLP-specific immune responses led to reduced peptide-specific antibody titers, we showed that CIES against peptide–VLP conjugates could be overcome by high coupling densities, repeated injections and/or higher doses of conjugate vaccine. Furthermore we dissected VLP-specific immunity by adoptively transferring VLP-specific antibodies, B-cells or Thelper cells separately into naive mice and found that the observed CIES against peptide–VLP conjugates was mainly mediated by carrier-specific antibodies.

Non-communicable, chronic diseases are currently the major cause of death and disability worldwide, and many of these maladies have reached epidemic proportions. According to the World Health Organization (WHO) these disorders, including cardiovascular and respiratory diseases, diabetes, obesity and cancer, now account for about half of the global disease burden as well as deaths worldwide. The WHO identifies comparatively few risk factors, namely smoking, alcohol abuse, obesity, high cholesterol and high blood pressure, as the cause of many of these chronic conditions. A new class of medicines, based on vaccine approaches, are now in clinical trials and hold significant promise to treat both risk factors and their associated chronic diseases.

T cell responses are regulated by the affinity/avidity of the T cell receptor for the MHC/peptide complex, available costimulation and duration of antigenic stimulation. Altered peptide ligands (APLs) are usually recognized with a reduced affinity/avidity by the T cell receptor and are often able to only partially activate T cells in vitro or may even function as antagonists. Here we assessed the ability of APLs derived from peptide p33 of lymphocytic choriomeningitis virus (LCMV) to mediate lysis of target cells in vivo, confer anti-viral protection and cause auto-immune disease. In general, in vitro cross-reactivity between APLs was rather limited, and even strongly cross-reactive cytotoxic T lymphocytes were only able to mediate moderate anti-viral protection. Partial protection was observed for infection with LCMV or low doses of recombinant vaccinia virus, while no reduced viral titers could be seen upon infection with high dose of vaccinia virus. In a transgenic mouse model expressing LCMV glycoprotein in the islets of the pancreas, APLs induced a transient insulitis but failed to induce autoimmune diabetes. Thus, effector functions induced by even highly homologous APLs are rather limited in vivo.

Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. In this perspective paper, we discuss the preclinical and clinical evidence that lithium has neuroprotective and neurotrophic effects, and furthermore, show that these effects may have great relevance for the optimal treatment of severe mood disorders. Lithium has been noted to have neuroprotective effects in cell culture, and in animal models of neurodegeneration such as stroke, Huntington's disease and Alzheimer's disease. This may be due to the findings that lithium regulates the expression and/or activity of numerous molecules and enzymes involved in neuroplasticity, neuroprotection and mitochondrial function including bcl-2, GSK-3 and the ERK/MAP kinase pathway. Emerging clinical evidence additionally suggests that lithium may have similar effects in patients; these findings include an increase in N-acetyl aspartate (NAA) and gray matter in patients following long-term lithium treatment. Together, the data has implications not only for the optimal treatment of severe mood disorders, but potentially also for the treatment of other, more classical, neurodegenerative disorders.

The immune system is fighting a constant war against pathogens in its own territory. This requires a potent arsenal for efficient control of pathogens but also requires tight regulatory mechanisms in order to avoid excessive collateral damage. Maintaining equilibrium is the daily challenge of the immune system. Interactions between pathogens, antigen-presenting cells (APCs) and lymphocytes are critical in this balancing act. Of particular importance for the generation of protective immune responses is the induction of activation programs in APCs directly by pathogens or by T cell derived factors, such as CD40L, RANKL or cytokines. In order to counterbalance overshooting immune responses, T cells and APCs secrete anti-inflammatory cytokines that are key for maintaining a healthy balance between protection and immunopathology.

The important role of B cells in protection against secondary viral infections has been recognized for a long time. Recent evidence suggests that B cells are also critically involved in protective immune reactions classically attributed to T cells. Specifically, antibodies have been documented to protect from many primary viral and parasitic infections and to be indispensable for the control of latent viral infections. Current vaccine strategies should take into account this pivotal role of antibodies.

The critical temperatures for 2D and 3D ferromagnetic Ising model are well-known using several methods. In the present paper we introduce a new technique: to study the time-series of different order parameters established by means of a single-spin Monte Carlo evolution of the system in a prefixed thermal bath. Temperature of the simulations is changed as to include a broad range around the critical temperature. We will show that the autocorrelation functions for different sizes of square and cubic lattices intersect in a way similar to the Binder cumulant of the same parameter. This opens new possibilities to study phase transitions by locating the order parameter and the time window leading to the best resolution. Moreover, we will also discuss initial applications of this technique to the Edwards–Anderson model in 2D.

Efficient T cell activation requires the engagement of a variety of ligand/receptor molecules in addition to T cell receptor (TCR)–major histocompatibility complex (MHC)/peptide interactions. The leukocyte function antigen 1 (LFA-1) and the CD28 glycoprotein have both been implicated in T cell activation. The present study dissects the roles of LFA-1 and CD28 in the activation of naive virus-specific CD8+ T cells. We demonstrate that LFA-1 facilitates T cell activation by lowering the amounts of antigen necessary for T cell activation. In the absence of LFA-1, 100-fold more antigen was required for T cell–antigen-presenting cell (APC) conjugation and all subsequent events of T cell activation, including TCR down-regulation, Ca2+-flux, T cell proliferation, and lytic effector cell induction. Thus, LFA-1 facilitates the functional triggering of TCRs by promoting adhesion of T cells to APCs but does not affect T cell activation otherwise. In contrast, CD28 played an entirely different role during T cell activation. CD28 reduced the number of TCRs that had to be triggered for T cell activation and allowed activation of T cells by low affinity ligands. CD28 but not LFA-1 prevented induction of T cell unresponsiveness after stimulation of TCRs. These results demonstrate that LFA-1 and CD28 exhibit distinct, nonoverlapping ways to influence T cell activation and suggest that the terms costimulation and signal 2 should be revisited.

Sensitivities of in vitro and in vivo assays for the detection of lymphocytic choriomeningitis virus (LCMV)-specific CTL were compared. Measurement of primary cytotoxicity was the least sensitive of all the tested assays. However, when the same 51Cr release assays were performed after in vitro restimulation, this in vitro method was found to be more sensitive than all of the five in vivo assays tested. Assessment of CTL-mediated protection against LCMV replication in spleens was most sensitive among the in vivo tests, followed by CTL-mediated resistance to intracerebral or intraperitoneal challenge infections with vaccinia-LCMV-recombinant virus. Inhibition of LCMV-induced choriomeningitis and of the footpad swelling reaction were least sensitive in detecting LCMV-specific CTL. As discussed, the presented sensitivity gradient may most probably be generalized.

Resume La frequence de la maladie thromboembolique justifie un traitement prophylactique dont le plus efficace est l'heparinisation. Mais ce traitement expose a des complications hemorragiques chirurgicales et « anesthesiqueslors des anesthesies locoregionales. Le risque de provoquer un saignement dans une region anatomiquement peu accessible est un des soucis de tout anesthesiste. La revue des cas rapportes d'anesthesies medullaires montre que le risque de saignement ou d'hematome medullaire est minime. Dans le doute, et si besoin est de choisir une anesthesie medullaire, il est judicieux d'evaluer et de comparer aussi bien les risques de complications thromboemboliques lies a l'intervention que les risques de complications hemorragiques associes a l'anesthesie medullaire.

Neutralization of the inflammatory cytokine interleukin-1β (IL-1β) is a promising new strategy to prevent the β-cell destruction, which leads to type 2 diabetes. Here, we describe the preclinical development of a therapeutic vaccine against IL-1β consisting of a detoxified version of IL-1β chemically cross-linked to virus-like particles of the bacteriophage Qβ. The vaccine was well tolerated and induced robust antibody responses in mice, which neutralized the biological activity of IL-1β, as shown both in cellular assays and in challenge experiments in vivo. Antibody titers were long lasting but reversible over time and not associated with the development of potentially harmful T cell responses against IL-1β. Neutralization of IL-1β by vaccine-induced antibodies had no influence on the immune responses of mice to Listeria monocytogenes and Mycobacterium tuberculosis. In a diet-induced model of type 2 diabetes, immunized mice showed improved glucose tolerance, which was mediated by improved insulin secretion by pancreatic β-cells. Hence, immunization with IL-1β conjugated to virus-like particles has the potential to become a safe, efficacious, and cost-effective therapy for the prevention and long-term treatment of type 2 diabetes.

Alzheimer's disease (AD) is characterized by progressive dementia, probably due to the accumulation of amyloid plaques in the brain. These plaques essentially consist of peptides [Aβ1–40 and Aβ1–42 (Aβ1–40/42)] derived from the amyloid precursor protein (APP). There is currently little symptomatic treatment and no curative therapy available, which makes AD one of the most distressing illnesses for both the patients and their families. A ray of hope for a possible therapy was provided recently by vaccination experiments in transgenic mice. Specifically, mice expressing mutant forms of human APP efficiently cleaved into Aβ1–40/42 peptides developed AD-like pathology. Surprisingly, both plaque burden and dementia could be reduced in these mice by active immunization for antibody induction using Aβ1–42 formulated in adjuvants as a vaccine (AN1792). Although the mechanism of plaque removal remains unclear, vaccination has proved to be efficient in a variety of APP-transgenic mouse models. Progress towards the clinic was rapid and ELAN pharmaceuticals, the front runner in the field, initiated a Phase II trial designed to demonstrate the efficacy of the therapy in humans. However, it was this particular study that brought hopes and progress to an abrupt halt because a few treated patients developed signs of aseptic encephalitis or meningitis following the second administration of the Aβ1–42 vaccine. Although little information has been released publicly, the symptoms were consistent with the induction of autoimmunity, an inherent risk and concern when vaccinating against self-antigens, such as Aβ1–42. Therefore this trial has been stopped.A detailed understanding of the immune responses induced in the vaccinated individuals is now crucial for further development of vaccination strategies that avoid these severe (albeit treatable) side-effects. It is of particular importance to understand the origin of the vaccine-induced disease, namely was it non-specifically caused by the adjuvants used, were the antibodies precipitating inflammation or were Aβ1-42-specific T cells responsible for the side-effects. Thankfully, the study by Hock et al. [1xSee all References][1] now offers the first insights into these questions. Of the 24 patients vaccinated in the study center in Zurich, almost all raised a significant antibody response. In addition, the antibodies recognized plaques of transgenic mice and patients, a requirement for plaque-removal in the mouse model. However, in one individual, aseptic encephalitis (meningitis) developed. Intriguingly, this particular patient had only raised a moderate antibody response. This observation indicates that specific antibodies alone might not be sufficient to cause disease in AD patients. Furthermore, the results are compatible with the view that T cells, rather than antibodies, are the major source of inflammation. This hypothesis is consistent with the fact that most, if not all, known inflammatory responses in the brain are caused by T cells rather than antibodies. Although it is obviously impossible to draw firm conclusions from a single patient, the data nevertheless suggest that vaccines against AD should aim at circumventing the induction of inflammatory T cell responses. Indeed, avoiding the use of adjuvants and restricting the size of the epitopes used for vaccination might offer valuable solutions for the generation of a viable vaccine against one of the most devastating diseases afflicting mankind.

Adaptive immunity is essential for protection against viral infections. Dependent on the type of virus, protection from primary infection can be mediated by antibodies and/or T cells, whereas protection from secondary infection is usually dependent on antibodies. Components of the innate immune system, for example, complement, are important in increasing antiviral protection. Complement-degradation products enhance targeting of viral antigens to lymphoid organs and increase both antiviral B- and T-cell responses. Therefore, at least for the complement system, innate immunity acts primarily in antiviral protection by enhancing adaptive immunity.Oehen et al. [1xMarginal zone macrophages and immune responses against viruses. Oehen, S. et al. J. Immunol. 2002; 169: 1453–1458PubMedSee all References][1] show that marginal zone and sinusoidal macrophages, specialized cell populations in the spleen and lymph nodes, respectively, are key for protection against lethal infection with vesicular stomatitis virus (VSV) or lymphocytic choriomeningitis virus (LCMV). Surprisingly, the protective function of the macrophages does not correlate with enhanced adaptive immunity. Specifically, mice deficient in marginal zone and sinusoidal macrophages mounted normal antibody and cytotoxic T-cell responses against VSV and LCMV, respectively. Yet, they could not control the virus, and died on infection. Interestingly, the macrophages were essential for early containment of the infection, at time points before adaptive immunity would kick in. Thus, rather than enhancing specific antiviral B- and T-cell responses, the macrophage populations seemed to be directly involved in antiviral protection.How could this happen? Both LCMV and VSV are efficiently filtered out from the circulation by marginal zone macrophages, probably through recognition mediated by scavenger or complement receptors. The ingested particles probably induce a defence program in the macrophage population, in part by activation of Toll-like receptor-3. On macrophage activation, viral particles might be digested in lysosomes rather than undergoing productive replication cycles. Thus, viral load is reduced early after infection, numerically facilitating the function of the adaptive immune system to remove the infectious particles. Much remains to be investigated on the biology of macrophages. Research on dendritic cells has revolutionized immunology but now it might be time to have a closer look at the properties and in vivo functions of macrophages.

Dendritic cells (DCs) are extremely potent at priming T-cell responses. However, whereas naive T cells recirculate between the blood, lymph nodes and spleen and do not usually enter peripheral tissues, a large proportion of DCs samples proteins and pathogens actively in the periphery but fails to enter primary lymphoid organs, where DCs would encounter naive T cells. It is only upon the activation of DCs, leading to the up-regulation of expression of CC-chemokine receptor 7 (CCR7) – the same chemokine receptor that is expressed on naive T cells – that DCs migrate from the periphery to the T-cell regions of lymphoid organs. Thus, factors and events that influence the up-regulation of expression of CCR7 and hence, the migration of DCs to lymphoid organs are key to the regulation of T-cell responses. Many factors of this kind have been identified and include host-derived proteins, such as CD40L, TNF and TRANCE/RANKL, as well as pathogen-derived molecules, such as LPS and DNA molecules rich in nonmethylated CpG motifs. In general, these factors induce the degradation of IκB and subsequent translocation of NF-κB into the nucleus of DCs, inducing the maturation program. Thus, the activation of NF-κB seems to be a key player in the regulation of the activation, maturation and migration of DCs.The paper by Bouchon et al. [1xA DAP12-mediated pathway regulates expression of CC-chemokine receptor 7 and maturation of human dendritic cells. Bouchon, A. et al. J. Exp. Med. 2001; 194: 1111–1122Crossref | PubMed | Scopus (244)See all References][1] identifies triggering receptor on myeloid cells 2 (TREM-2) as a novel factor involved in the regulation of DC maturation. TREM-2 is a recently identified TREM family member of the Ig superfamily. Stimulation of TREM-2 is shown to induce a distinct maturation program in DCs, leading to the up-regulation of expression of CCR7 and some costimulatory molecules, and prolonged cellular survival. However, in contrast to CD40L or LPS, TREM-2 fails to induce the up-regulation of expression of adhesion molecules, such as ICAM, and does not induce the down-regulation of expression of receptors involved in the capture of antigen, such as the mannose receptor. Moreover, in contrast to previously known activators of DCs, TREM-2 does not stimulate the NF-κB pathway or the stress-activated protein kinases (SAPK/p38 or JNK), but seems to operate exclusively through stimulation of the MAP kinase ERK. Thus, TREM-2 induces a unique maturation program in DCs, most probably owing to selective activation of the ERK pathway. Interestingly, TREM-2 is shown to interact with the adapter molecule DAP12, which is known to recruit ZAP70 and p72/syk through its ITAM motifs. Thus, DAP12 relays TREM-2 signals to the ERK pathway and is probably responsible for the unique phenotype of TREM-2-activated DCs.The findings by Bouchon et al. have major implications for our understanding of the regulation of DC trafficking and induction of T-cell responses. First, it is becoming increasingly evident that the maturation of DCs is not an all or none event but might occur in several distinct ways, dependent upon the types of signaling pathways triggered within the cell. The present study indicates that the balance beween NF-κB and ERK signals might be of key importance for this process. Second, it is known that the DCs of DAP12-deficient mice fail to migrate to lymphoid organs from mucosal and epithelial tissues, and exhibit severely impaired Th1 responses. This suggests strongly an important role for TREM-2 in regulating T-cell responses in vivo. Third, recent evidence indicates that a proportion of mature DCs found in lymphoid organs is highly efficient at capturing antigens and processing them for MHC-class-I- and class-II-restricted presentation. Because DCs activated by TREM-2 up-regulate their expression of costimulatory molecules and CCR7, they would be perceived generally as fully mature cells. Nevertheless, these DCs maintain their high-level expression of receptors involved in antigen capture. Thus, TREM-2 might be involved in the normal turnover of DCs and might be responsible for the presence of mature DCs, fully capable of antigen processing, in lymphoid organs. A specific ligand for TREM-2 has not been discovered so far and the elucidation of its nature will be a major goal for the future.

The activation of T cells requires the continual engagement of T-cell receptors (TCRs) for several hours. However, most signal-transduction molecules triggered by the TCR seem to be activated only transiently. They are maximally phosphorylated for only a few minutes, after which time the degree of phosphorylation decreases. How, then, does a T cell sense long-term stimulation? It has been postulated that T cells might use a counting mechanism that determines the number of TCRs triggered over time. The easiest way for the T cell to do this would be to use a molecule that accumulates over time, its accumulation being dependent upon the intensity and duration of TCR signaling. Thus, the amount of this molecule present in the cell would be a measure of the total TCR-mediated signal that the cell has received.The paper by Rosette et al. 1xThe impact of duration versus extent of TCR occupancy on T-cell activation: a revision of the kinetic proofreading model. Rosette, C. et al. Immunity. 2001; 15: 59–70Abstract | Full Text | Full Text PDF | PubMed | Scopus (157)See all References1 suggests a role for phosphorylated c-Jun (pc-Jun) as a ‘counter’ molecule. The authors examined how partial T-cell agonists, recognized by the TCR with intermediate affinity, can trigger T-cell activation. They identified one peptide that failed to stimulate the early events of T-cell activation, such as Ca2+ flux or phosphorylation of members of the MAP kinase family, but that could stimulate later events of T-cell activation, such as the up-regulation of expression of CD69 (albeit with delayed kinetics). Apparently, the peptide induced a weak signal that accumulated over time and eventually reached the threshold value required for the up-regulation of expression of CD69. Strikingly, the authors also found a signal-transduction molecule that accumulated over time if T cells were stimulated with either a high- or low-affinity peptide. This molecule was identified as pc-Jun. As would be expected for a ‘counter’, the kinetics of the accumulation of pc-Jun paralleled those of T-cell activation, and its accumulation occurred more slowly upon stimulation with the low-affinity peptide. Thus, the amount of pc-Jun present in a T cell seems to reflect the integral of the TCR-mediated signals.These results have interesting implications for T-cell activation in general. First, they explain the transient nature of the activation of intracellular signaling molecules and the requirement for up to 12 hours of stimulation for T-cell activation. Second, the results are compatible with triggering of the TCR being an ‘all-or-nothing’ event. The observations do not indicate that the partial phosporylation of CD3-ζ chains following stimulation with weak ligands has an important function. Rather, it is suggested that weak ligands trigger full TCR-mediated signals with low probability. These signals accumulate over time and lead to a sufficient level of pc-Jun for T-cell activation to occur. The signaling unit of the T cell remains to be determined, but a TCR dimer present for minimal time seems highly compatible with the data.

Nonobese diabetic (NOD) mice spontaneously develop autoimmune diabetes, bearing close resemblance to the human condition. The disease is mediated by auto-specific T cells, which infiltrate the pancreatic islets and destroy insulin-producing β cells. A hallmark of the disease is the de novo generation of lymph-node-like structures in the pancreas, which are essential for progression of the disease. A large body of evidence implicates lymphotoxin (LT) in the formation of these lymphoid structures and the production of follicular dendritic cells. In support of this notion, the ectopic expression of LT can result in the in situ generation of lymph-node-like organs in the periphery. Hence, it was supposed that the formation of organized lymphoid structures in the pancreas of NOD mice might be regulated by LT.The paper by Wu et al. 1xReversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. Wu, Q. et al. J. Exp. Med. 2001; 193: 1327–1332Crossref | PubMed | Scopus (88)See all References1 addresses the role of LT in autoimmune diabetes in NOD mice. Using a LTβ-receptor Ig fusion molecule, they blocked the function of LTβ at various time points during the life of NOD mice. Perhaps not surprisingly, they found that blocking LTβ in 3–4-week-old mice for approximately six weeks prevented the induction of diabetes. However unexpectedly, they were also able to prevent the induction of diabetes in older mice that already exhibited insulitis at the onset of therapy. Moreover, treatment for only three weeks was sufficient to reduce the severity of diabetes dramatically and essentially, reverse the insulitis. Thus, blocking LTβ was able to prevent diabetes even if therapy was started after the onset of autoimmunity.These observations indicate that in NOD mice, LT functions as a ‘master’ cytokine essential for the de novo formation of lymph-node-like structures in the pancreas during the disease process. The results make two important points. First, the presence of auto-specific T cells seems insufficient to induce autoimmunity. Target organs might need to be chronically inflamed and it seems that the generation of lymphoid follicles is necessary for overt disease. Thus, although priming of self-specific T cells might occur in the lymph nodes, the stimulation of T cells in the peripheral lymph-node-like structures appears to be essential for progression of the disease. Second, the results might be relevant to the therapy of type I diabetes in humans. Although it was not possible to reverse disease in mice with pre-existing diabetes, short-term therapy was able to cure mice exhibiting severe insulitis. Thus, the close monitoring of people at risk of developing type I diabetes might allow therapy to commence early enough to prevent or, at least, delay the onset of disease. Moreover, blocking LTβ might be a promising treatment for other autoimmune diseases, including Hashimoto's thyroiditis and arthritis.

BSE, scrapie and new variant Creutzfeldt–Jakob disease are caused by exposure to pathological forms of prion protein (PrPSc). Following amplification in the periphery, PrPSc invades the nervous system by an as-yet-unknown mechanism. Follicular dendritic cells (FDCs) are the major site of PrPSc accumulation outside of the CNS. Indeed, FDCs play a pivotal role in disease progression, as animals lacking FDCs are protected from disease. Under physiological conditions, FDCs ‘fish’ Ags from the circulation and store them in their native form on the cell surface; these trapped Ags are presented to specific B cells for the initiation and maintenance of Ab responses. This Ag-trapping mechanism might occur through Fc receptors or the complement receptors CD21 and/or CD35. Thus, a functional complement cascade and/or Ab system is required for the efficient capture of Ag by FDCs.Two articles by Mabbott et al. 1xTemporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Mabbott, N.A. et al. Nat. Med. 2001; 7: 485–487Crossref | PubMed | Scopus (176)See all References1 and Klein et al. 2xComplement facilitates early prion pathogenesis. Klein, M.A. et al. Nat. Med. 2001; 7: 488–492Crossref | PubMed | Scopus (247)See all References2 assess the role of complement and Fc receptors in the progression of murine scrapie. The absence of C3, a crucial component of both the classical and alternative pathways of the complement cascade, significantly delayed disease progression and reduced the burden of PrPSc in the periphery. A deficiency of complement receptors CR1 and CR2 (CD21 and CD35, respectively) had a similar impact on disease progression, suggesting that C3 is responsible for the deposition of PrPSc through complement receptors. Interestingly, the absence of PrPSc-specific Abs and a variety of Fc receptors (FcγRI–FcγRIII) had no influence on the disease. This is consistent with the observation that no anti-PrPSc Abs can be detected in infected animals, probably because the host's immune system remains unresponsive to PrPSc. Nevertheless, it remains possible that the combination of a deficiency in Fc receptors and complement might result in a further reduction in the replication of PrPSc. This is in line with the observation that the requirement for complement for disease progression is not absolute, as high doses of PrPSc were able to induce scrapie with normal kinetics in complement-deficient mice. This is reminiscent of some anti-viral B-cell responses, where complement-dependency can be overcome by high Ag-load.These observations demonstrate a pivotal, albeit not absolute, role for complement in the induction of scrapie, and suggest that temporal elimination of components of the complement cascade might be a potential therapy for infected individuals. The studies also make an interesting case for how infectious agents, including, in this case, the simplest-known agent, can exploit the properties of the immune system for their own purposes. FDCs store native Ags and present them to B cells; to perform this task, they have evolved receptors that bind foreign Ags and mechanisms that protect the Ags from degradation and phagocytosis by other cell types. It is precisely this property of FDCs that is exploited by the scrapie-agent and allows PrPSc not only to persist safely, but even to replicate, within the heart of the immune system. It is hard to believe that all this is achieved by a protein that apparently does not even carry any genetic information!

Specific T-cell activation usually requires two signals: an antigen-specific signal 1 and a costimulatory signal 2. The best described costimulatory molecule is CD28, which interacts with B7 family members CD80/CD86 on professional antigen-presenting cells (APCs). Accordingly, CD28-deficient mice are unable to mount relevant T-cell responses to a variety of antigens. Nevertheless, many pathogens, in particular viruses, have been shown to induce reasonably strong T-cell responses in the absence of CD28. Alternative costimulatory molecules have therefore been postulated from these findings that might be able to replace CD28, particularly after infection. As a result of its homology with CD28, ICOS (inducible costimulator) was an obvious candidate for such an alternative costimulatory molecule.Three articles by Dong et al. 1xICOS co-stimulatory receptor is essential for T-cell activation and function. Dong, C et al. Nature. 2001; 409: 97–101Crossref | PubMed | Scopus (596)See all References, McAdams et al. 2xICOS is critical for CD40-mediated antibody class switching. McAdam, A.J et al. Nature. 2001; 409: 102–105Crossref | PubMed | Scopus (491)See all References and Tafuri et al. 3xICOS is essential for effective T-helper cell responses. Tafuri, A et al. Nature. 2001; 409: 105–109Crossref | PubMed | Scopus (512)See all References have assessed the role of ICOS in T-cell activation using ICOS-deficient mice. All three groups reported a dramatically impaired priming of T helper (Th) cells, consistent with the idea that an interaction of ICOS with B7h/B7RP-1 on APCs delivers a costimulatory signal into T cells that enhances their activation and boosts T-cell-dependent antibody responses. Interestingly, if assessed in vitro, secretion of Th2 cytokines, in particular interleukin (IL)-4 and IL-13, was strongly reduced whereas secretion of Th1 cytokines remained unaltered or was even increased. These data suggested that ICOS was selectively costimulating Th2 cytokines. Nevertheless, the observation that both IgG1 and IgG2a antibody subclasses were reduced after immunization might suggest that Th1 responses are also impaired in ICOS-deficient mice in vivo, a notion consistent with the earlier finding that anti-viral Th1 responses were reduced if ICOS was blocked with an Ig fusion molecule. Intriguingly, Dong et al. 1xICOS co-stimulatory receptor is essential for T-cell activation and function. Dong, C et al. Nature. 2001; 409: 97–101Crossref | PubMed | Scopus (596)See all References have shown that ICOS-deficient mice are hyper-susceptible to autoimmune encephalomyelitis (EAE), a multiple-sclerosis-like disease in mice, indicating that ICOS might trigger the production of anti-inflammatory cytokines. This might further indicate that ICOS is involved in the regulation of cytokine production and effector function of Th cells in vivo. Because IL-10 production was not affected in ICOS-deficient mice, it was speculated that exacerbated disease was caused by a reduced production of IL-13.These observations constitute the basis for the importance of ICOS as a novel costimulatory molecule. What is the difference then between CD28 and ICOS? CD28 is constitutively expressed on T cells, whereas ICOS-expression is restricted to activated T cells. Similarly, B7-family members are expressed on resting dendritic cells (although expression increases upon activation), whereas expression of B7h/B7RP-1 occurs primarily on non-professional APCs, in particular upon exposure to inflammatory stimuli. Thus, it is tempting to speculate that CD28 might be responsible for initial activation of T cells by dendritic cells in primary lymphoid organs. By contrast, ICOS might function to allow for sustained T-cell effector function in the periphery, particularly in inflamed tissues. However, for a therapeutic use of ICOS, it will be mandatory to dissect the anti-inflammatory properties of this molecule observed in the EAE model versus its pro-inflammatory properties observed earlier in a murine model of asthma.