Specific Tolerance Research Articles

Ultraviolet B irradiation in the prevention of alloimmunization in a dog platelet transfusion model.

Alloimmune platelet (PLT) refractoriness remains a significant problem for chronically transfused patients with thrombocytopenia. In a dog PLT transfusion model, we evaluated ultraviolet B irradiation (UV-B) of donor PLTs-either alone or in combination with centrifuge leukoreduction (C-LR) or filtration leukoreduction (F-LR)-to prevent refractoriness to donor PLTs and to induce tolerance to standard (STD) PLTs from the same donor or to tertiary donors. Recipient acceptance rates for C-LR donor PLT transfusions were 14%, F-LR were 33%, and UV-B irradiated were 45% with no significant differences among the treatments given to the donor's PLTs. Adding UV-B irradiation to C-LR or F-LR PLTs increased acceptance rates to 50 and 68% (p = 0.02 and p = 0.05), respectively, comparing single treatments to the combined treatments. After a recipient had accepted any type of UV-B-treated donor PLTs, specific tolerance to subsequent transfusions of the same donor's STD PLTs averaged 65%. Nonspecific tolerance to third-party donor's STD PLTs averaged 36% if they had accepted their initial donor's treated PLTs but was only 4% (p < 0.001) if they had rejected these PLTs. Combining UV-B irradiation with a method of leukoreduction produces additive effects on prevention of alloimmune PLT refractoriness.

Crystal structure and identification of a key amino acid for glucose tolerance, substrate specificity, and transglycosylation activity of metagenomic β-glucosidase Td2F2.

β-Glucosidase Td2F2 isolated from a compost metagenome has high glucose tolerance and transglycosylation activity. In this study, we determined the high-resolution crystal structure of Td2F2. It has a unique structure at the -1 subsite that is important for substrate specificity but not for glucose tolerance. To elucidate the mechanism(s) of glucose tolerance, we isolated a glucose-sensitive Td2F2 mutant using random mutagenesis. In this mutant, Asn223 residue located between subsites +1 and +2 was mutated. The Asn223 mutation resulted in reduced glucose tolerance and transglycosylation activity, and drastically changed substrate specificity. These results indicate that the structure between subsites +1 and +2 is critical for the glucose tolerance and substrate specificity of Td2F2. Our findings shed light on the glucose tolerance and transglycosylation activity mechanisms of glycoside hydrolase family 1 β-glucosidases. The atomic coordinates and structure factors (codes 3WH5, 3WH6, 3WH8, 3WH7, 5AYB, and 5AYI) have been deposited in the Protein Data Bank (http://wwpdb.org/).

Suppression of established food allergy by a combination of anti-TSLP, anti-IL-33, and anti-IL-25 monoclonal antibodies.

Abstract Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. In contrast, we recently reported (JACI, 131:442–50, 2013) that Ag-specific, IgE-mediated food allergy (FA) can be induced when a protein Ag is repeatedly ingested with a widely used nutrient, medium chain triglycerides (MCT), without any additional sensitization. Mice that have been repeatedly inoculated orally with MCT plus egg white (EW) develop a Th2 cytokine and an IgE response as well as shock (hypothermia) following oral EW + MCT challenge. Because MCT ingestion induces increased intestinal epithelial cell expression of the pro-Th2 cytokines TSLP, IL-25 and IL-33, we investigated the importance of these cytokines in establishing and maintaining FA. We found that treatment with neutralizing mAbs to any of the pro-Th2 cytokines could suppress MCT + EW-induced FA development, with aTSLP mAb causing near-total suppression and aIL-25 and aIL-33 each causing considerable suppression. In contrast, treatment with aTSLP mAb, by itself, had little effect on established FA to EW. Treatment of established FA with combinations of mAbs to any two pro-Th2 cytokines had a partial suppressive effect, with the combination of aTSLP + aIL-33 being most suppressive. Simultaneous treatment with mAbs to all three pro-Th2 cytokines caused complete loss of the hypothermia response to EW + MCT challenge and considerably reduced IL-4, IL-13, IgE, and mouse mast cell protease 1 responses. Thus, all three pro-Th2 cytokines are essential for FA induction, but these cytokines are somewhat redundant for FA maintenance in our model. These results provide a better understanding of the FA mechanisms and lead to the development of novel therapies.

Induction of donor-specific immune tolerance using bioengineered thymus organoid

Abstract Extended use of immunosuppression is a major setback in organ transplantation. Hence, establishment of donor specific immune unresponsiveness, without the need of immunosuppression, is critical and remains a major challenge. Immunological tolerance is known to occur through two main mechanisms: central (thymus) and peripheral. Our lab has recently reported that bioengineered thymus organoids, made of de-cellularized thymus scaffolds populated with thymic epithelial cells (TECs), can successfully support T-cell generation in athymic nude mice. Here, we aim to test the hypothesis that transplantation of bioengineered thymus, incorporated with donor TECs, can induce central tolerance to donor antigens. Thymus scaffold were reconstructed with either TECs harvested from F1 offspring of B6 (H-2b) and NOD (H-2b/g7) or TECs from both B6 and CBA/J (H-2k) mixed in 1:1 ratio. These reconstructed thymus organoids are transplanted to the B6. Nude recipient, that are subsequently challenged with syngeneic, allogeneic and third party skin graft. Results from recipients with transplanted bioengineered thymus consisting F1 TECs demonstrated successful engraftment of skin transplants from both syngeneic (B6) and allogeneic (B6.H-2b/g7) whereas, clear rejection of the third party (CBA/J). Similarly, we observed prolonged survival of allograft skin (CBA/J) than third party (Balb/C) in recipient mice with reconstructed thymus organoids containing TECS from both donor (B6) and recipient (Balb/c). Furthermore, immune unresponsiveness to allograft was shown in MLR assay. Overall, our findings suggest reconstructed thymus-containing donor TECs could potentially have clinical application to induce-donor specific immune tolerance.

Risk measures and their application to staffing nonstationary service systems

In this paper, we explore the use of static risk measures from the mathematical finance literature to assess the performance of some standard nonstationary queueing systems. To do this we study two important queueing models, namely the infinite server queue and the multi-server queue with abandonment. We derive exact expressions for the value of many standard risk measures for the Mt/M/∞, Mt/G/∞, and Mt/Mt/∞ queueing models. We also derive Gaussian based approximations for the value of risk measures for the Erlang-A queueing model. Unlike more traditional approaches of performance analysis, risk measures offer the ability to satisfy the unique and specific risk preferences or tolerances of service operations managers. We also show how risk measures can be used for staffing nonstationary systems with different risk preferences and assess the impact of these staffing policies via simulation.

The need for specific tolerance assessments of baby products: The diaper barrier cream experience

The need for specific tolerance assessments of baby products: The diaper barrier cream experience

Dietary n-3 long chain polyunsaturated fatty acids in allergy prevention and asthma treatment

The rise in non-communicable diseases, such as allergies, in westernized countries links to changes in lifestyle and diet. N-3 long chain polyunsaturated fatty acids (LCPUFA) present in marine oils facilitate a favorable milieu for immune maturation and may contribute to allergy prevention. N-3 LCPUFA can suppress innate and adaptive immune activation and induce epigenetic changes. Murine studies convincingly show protective effects of fish oil, a source of n-3 LCPUFA, in food allergy and asthma models. Observational studies in human indicate that high dietary intake of n-3 LCPUFA and low intake of n-6 PUFA may protect against the development of allergic disease early in life. High n-6 PUFA intake is also associated with an increased asthma risk while n-3 LCPUFA may be protective and reduce symptoms. The quality of the marine oil used has impact on efficacy of allergy prevention and several observations link in particular n-3 LCPUFA DHA to allergy suppression. Randomized controlled trials indicate that optimal timing, duration and dosage of n-3 LC-PUFA is required to exert an allergy protective effect. Supplementation during early pregnancy and lactation has shown promising results regarding allergy prevention. However these findings should be confirmed in a larger cohort. Although clinical trials in asthma patients reveal no consistent clinical benefits of n-3 LCPUFA supplementation on lung function, it can suppress airway inflammation. Future food-pharma approaches may reveal whether adjunct therapy with dietary n-3 LCPUFA can improve allergy prevention or immunotherapy via support of allergen specific oral tolerance induction or contribute to the efficacy of drug therapy for asthma patients.

Potentially toxic elements in serpentine soils and plants from Tuscany (Central Italy). A proxy for soil remediation

Serpentine soils have relatively high concentrations of potentially toxic elements (PTEs) (Co, Cr, Cu, Fe, Ni) but generally low amounts of major nutrients. They often bear a distinctive vegetation, with specific tolerance to PTEs, and a frequently-used approach to understanding serpentine ecology and related environmental hazard has been the chemical analysis of soils and plants. In this paper we report the results of a study on serpentine soils and serpentinophytes from different outcrops in central Italy.In this study, serpentine soils have neutral to sub-alkaline pH (range 6.05–8.15), sandy loam to clay loam textural class, paucity of essential nutrients. PTEs are more abundant in subsoil than in topsoil, consistently with the nature of parent material. Average content of Ni is 2342, Cr=3502, Co=149, Cu=28, Mn=1754, Zn=91mgkg−1, respectively.Trace elements in serpentine vegetation (both obligate and facultative serpentinophytes) are generally accumulated in roots, but some species (e.g. Alyssum bertolonii) are able to (hyper)accumulate metals (up to 2118mgNikg−1) in the aerial parts, without showing toxic features, owing to a tolerance mechanism to very high metal concentrations.Serpentinophytes, therefore, could represent proxies for plants used in remediation of metal-contaminated soils with both phytoextraction and phytostabilization, and in phytomining as well.

In situ expansion of T cells that recognize distinct self-antigens sustains autoimmunity in the CNS.

Polyspecific T cells recognizing multiple distinct self-antigens have been identified in multiple sclerosis and other organ-specific autoimmune diseases, but their pathophysiological relevance remains undetermined. Using a mouse model of multiple sclerosis, we show that autoimmune encephalomyelitis induction is strictly dependent on reactivation of pathogenic T cells by a peptide (35-55) derived from myelin oligodendrocyte glycoprotein (MOG). This disease-inducing response wanes after onset. Strikingly, the progression of disease is driven by the in situ activation and expansion of a minority of MOG35-55-specific T cells that also recognize neurofilament-medium (NF-M)15-35, an intermediate filament protein expressed in neurons. This mobilization of bispecific T cells is critical for disease progression as adoptive transfer of NF-M15-35/MOG35-55 bispecific T cell lines caused full-blown disease in wild-type but not NF-M-deficient recipients. Moreover, specific tolerance through injection of NF-M15-35 peptide at the peak of disease halted experimental autoimmune encephalomyelitis progression. Our findings highlight the importance of polyspecific autoreactive T cells in the aggravation and perpetuation of central nervous system autoimmunity.

Switching long acting antipsychotic medications to aripiprazole long acting once-a-month: expert consensus by a panel of Italian and Spanish psychiatrists

ABSTRACTIntroduction: Aripiprazole long acting once-monthly (AOM) is a long acting atypical antipsychotic with proven efficacy in schizophrenia and with a pharmacological and a side effect profile that is different from other antipsychotics. These and other characteristics make AOM a possible alternative in patients requiring a change in long acting antipsychotic treatment due to issues such as lack of efficacy or persistent side effects. Both clinical and pharmacological factors should be considered when switching antipsychotics, and specific guidelines for long acting antipsychotic switching that address all these factors are needed.Areas covered: A panel of Italian and Spanish experts in psychiatry met to discuss the strategies for the switch to AOM in patients with schizophrenia. Real life clinical experiences were shared and the clinical strategies to improve the likelihood of success were discussed.Expert Opinion: Due to its specific pharmacological and tolerability profile, AOM represents a suitable alternative for patients with schizophrenia requiring a switch to a new LAI treatment because of lack of efficacy or persistent side effects from another LAI. Possible strategies for the switch to AOM are presented in this expert consensus paper in an attempt to provide guidance throughout the entire switching process

Geometry Optimisation for 2D Cutting: A Quadratic Programming Approach

A novel approach to geometry optimisation in the field of 2D cutting is presented in this paper. Set point generation inside of state of the art CNCs is divided in the preparation of the geometry and the feed rate generation. The feed rate generation is influenced by parametric derivatives of the given geometry. Due to this fact, the shaping of a B-Spline is carried out by optimisation of the weighted sum of parametric derivatives while the given manufacturing tolerances are maintained. For the sake of robustness, the arising optimisation problem is formulated as a quadratic program with linear constraints, one which can be solved with great efficiency by using an interior point method. In contrast to state of the art methods, the discrete formulation of the problem allows for a pointwise specification of the manufacturing tolerance. Depending on the manufacturing process, the given manufacturing tolerance is shared by different axes, which is shown for a 2D cutting geometry. An application example shows that the geometry optimisation leads to an increase in machining productivity over state of the art methods.

Physiological and Biochemical Responses of Eight Eucalyptus Species to Salinity Stress

The effect of salt stress on the pysiological and biochemical responses of the seedlings of eight Eucalyptus species viz. E. kingsmillii, E. tetragona, E. salubris, E. occidentali, E. microtheca, E. camaldulensis, E. globules and E. sargentii was analyzed. Four month-old seedlings grown in greenhouse were watered by five levels of salt solution (0, 50, 100, 150 and 200 mM of NaCl) in five replications with a factorial experimental design. The results indicated that salinity delayed and inhibited the seedlings’ growth after one month, and induced gradual decline in most of the criteria such as leaf area, relative water content and specific leaf area. Moreover, a significant reduction of chlorophyll a, b and total chlorophyll content was observed. Salinity stress raised the content of soluble sugars, proline and glycine betaine. Eucalyptus sargentii as the most tolerant species had the optimum growth up to 200 mM NaCl but E. globulus presented the most sensitive species to salinity stress. At 200 mM NaCl, proline and glycine beatine raised to 10.57 and 27 μg g in the tolerant species (E. sargentii), respectively while proline in the sensitive species (E. globulus) dropped to 0.003 μg g. These results suggest that high tolerance of E. sargentii to salinity stress is closely related to lower specific leaf area and enhancement of compatible solutions such as proline, soluble sugar, glycine beatine. This would encourage the possibility of propagating E. sargentii in the southern coastal area of Iran. Furthermore, these results provided further biochemical support for the specific abiotic stress tolerance mechanism of Eucalyptus species.

Immunothérapies innovantes des maladies allergiques respiratoires

Allergen immunotherapy (AIT) is an effective method in the treatment of respiratory allergic diseases (asthma, rhinitis and conjunctivitis). In addition to reducing symptoms, AIT can alter the course of allergic disease and remains efficient long after it has been discontinued by inducing specific tolerance to the allergen. In current clinical practice, immunotherapy is administered by subcutaneous or sublingual routes. The duration of efficacy is 7 to 12 years. It can prevent the development of both asthma and sensitization to new allergens. Despite recent progresses, other approaches are needed, especially for allergies (atopic dermatitis, food allergies). The new AIT improvement approaches involve the use of adjuvants or recombinant allergies, peptides and new routes of administration.

Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease.

The main limitations to the success of transplantation are the antigraft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the antidonor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system. Stem Cells 2016;34:1142-1150.

Effect of mTORC1/mTORC2 inhibition on T cell function: potential role in graft-versus-host disease control.

The mechanistic target of rapamycin (mTOR) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft-versus-host disease (GvHD). Despite its partial ability to block mTOR pathway, the mTORC1 inhibitor rapamycin has shown encouraging results in the control of GvHD. Therefore, we considered that simultaneous targeting of both mTORC1 and mTORC2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in GvHD control. To assess this assumption, we have used the dual mTORC1/mTORC2 inhibitors CC214-1 and CC214-2. In vitro studies confirmed the superior ability of CC214-1 versus rapamycin to block mTORC1 and mTORC2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC214-1 was more efficient in inhibiting naïve T cell activation and the expression of T-cell activation markers. In addition, CC214-1 induced specific tolerance against alloantigens, while preserving anti-cytomegalovirus response. Finally, in a mouse model of GvHD, the administration of CC214-2 significantly improved mice survival and decreased GvHD-induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC214-1 on T lymphocytes and illustrates the role of CC214-2 in the allogeneic transplantation setting as a possible GvHD prophylaxis agent.

Flaw tolerance of metallic glasses

The flaw tolerance of bulk metallic glasses (BMGs) is evaluated using a thermoplastic synthesis approach. We found that flaw tolerance quantified by the notch toughness decreases apparently with decreasing radius until a critical value. Below this critical value, measured notch toughness is independent of its radius, revealing a flaw tolerance behavior of BMGs. We explain such flaw tolerance by a critical plastic zone originating from the BMGs' inherent crack tip blunting capability. This zone defines a characteristic distance over which stable shear banding plastic process develops prior to fracture instability. The specific characteristic distance and crack blunting capability vary widely among BMGs, which rationalizes the vast variety in their fracture behavior and suggest specific flaw tolerance. Our finding is encouraging for BMGs' structural applications since flaws smaller than the critical value are increasingly difficult to avoid but are “indistinguishable” in their influence to fracture toughness.

Verification of dimensional stability on ITER blanket shield block after stress relieving

The tight tolerance requirement is one of key issue to manufacture the ITER blanket shield blocks (SBs) which have many interfaces with the First Wall (FW) and Vacuum Vessel (VV). Manufactured SB shall be satisfied with general tolerances (Class “C” of ISO 2768-1 and “L” of ISO 2768-2) and specific tolerance in 2D general assembly drawings. In order to fulfill the tight tolerance requirements in the final stage of SB, stress relieving after welding operations in the manufacturing process shall be performed. Hot helium leak test, Post Welding Heat Treatment (PWHT) and three-dimensional inspection before and after heat treatment were implemented by using the Full Scale Prototype (FSP) of SB in the framework of domestic R&D activities. The hot He leak test was performed at 250°C for 30min, and the result was satisfied the requirements. PWHT was carried out at 400°C for 24h by brazing furnace with test chamber. The deformation value before and after was measured by contact type coordinate measuring machine. The objective of this study is to verify dimensional stability of SB after stress relieving. The results will support to determine the machining allowance prior to welding process.

Make or buy analysis model based on tolerance allocation to minimize manufacturing cost and fuzzy quality loss

The specification of tolerances has a significant impact on the quality of product and final production cost. The company should carefully pay attention to the component or product tolerance so they can produce a good quality product at the lowest cost. Tolerance allocation has been widely used to solve problem in selecting particular process or supplier. But before merely getting into the selection process, the company must first make a plan to analyse whether the component must be made in house (make), to be purchased from a supplier (buy), or used the combination of both. This paper discusses an optimization model of process and supplier selection in order to minimize the manufacturing costs and the fuzzy quality loss. This model can also be used to determine the allocation of components to the selected processes or suppliers. Tolerance, process capability and production capacity are three important constraints that affect the decision. Fuzzy quality loss function is used in this paper to describe the semantic of the quality, in which the product quality level is divided into several grades. The implementation of the proposed model has been demonstrated by solving a numerical example problem that used a simple assembly product which consists of three components. The metaheuristic approach were implemented to OptQuest software from Oracle Crystal Ball in order to obtain the optimal solution of the numerical example.

English

To assess modifications in baseline specific IgE- and anti-IgE- and antigen-specific-mediated basophil activation in egg-allergic children. The values were compared before and after the children completed specific oral tolerance induction (SOTI) with egg. We studied 28 egg-allergic children who completed SOTI with egg. The basophil activation test and specific IgE determinations with egg white, ovalbumin, and ovomucoid were performed in all 28 children. A decrease in antigen-specific activation with egg white, ovalbumin, and ovomucoid was observed only at the 2 lowest concentrations used (5 and 0.05 ng/mL). Baseline activation was higher in patients with multiple food allergies and in those who developed anaphylaxis during SOTI; this activation decreased in both groups after completion of SOTI. A significant decrease was also observed in specific IgE values for egg white, ovalbumin, and ovomucoid after tolerance induction. Food tolerance induction is a specific process for each food that can be mediated by immunologic changes such as a decrease in specific IgE values and in specific and spontaneous basophil activation.

ABH-Glycan Microarray Characterizes ABO Subtype Antibodies: Fine Specificity of Immune Tolerance After ABO-Incompatible Transplantation.

Organ transplantation from ABO blood group-incompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century-old assay used clinically, does not discriminate subtype-specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO-glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor-specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO-compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens-the only ABH antigen subtypes expressed in heart tissue-were absent, demonstrating the fine specificity of B cell tolerance to donor/graft blood group antigens. In contrast to the hemagglutination assay, the ABO-glycan microarray allows detailed characterization of donor-specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection.