B cells are essentially described for their capacity to produce antibodies ensuring anti‐infectious immunity or deleterious responses in the case of autoimmunity or allergy. However, abundant data ...described their ability to restrain inflammation by diverse mechanisms. In allergy, some regulatory B‐cell subsets producing IL‐10 have been recently described as potent suppressive cells able to restrain inflammatory responses both in vitro and in vivo by regulatory T‐cell differentiation or directly inhibiting T‐cell‐mediated inflammation. A specific deficit in regulatory B cells participates to more severe allergic inflammation. Induction of allergen tolerance through specific immunotherapy induces a specific expansion of these cells supporting their role in establishment of allergen tolerance. However, the regulatory functions carried out by B cells are not exclusively IL‐10 dependent. Indeed, other regulatory mechanisms mediated by B cells are (i) the production of TGF‐β, (ii) the promotion of T‐cell apoptosis by Fas–Fas ligand or granzyme‐B pathways, and (iii) their capacity to produce inhibitory IgG4 and sialylated IgG able to mediate anti‐inflammatory mechanisms. This points to Bregs as interesting targets for the development of new therapies to induce allergen tolerance. In this review, we highlight advances in the study of regulatory mechanisms mediated by B cells and outline what is known about their phenotype as well as their suppressive role in allergy from studies in both mice and humans.
A novel method was tested for improving tree breeding strategies that integrate quantitative and population genetics based on range‐wide reciprocal transplant experiments. Five reciprocal common ...garden tests of Populus tremuloides were investigated including 6450 trees across western Canada focusing on adaptation traits and growth. Both genetic parameters and home‐site transplant models were evaluated. We found a genetic trade‐off between growth and early spring leaf flush and late fall senescence. Coefficients of phenotypic variation (CVp) of cell lysis (CL), a measure of freezing injury, shrank from 0.28 to 0.10 during acclimation in the fall, and the CVp slope versus the freezing temperature was significantly different from zero (R2 = 0.33, p = .02). There was more between‐population genetic variation in fall phenology than in spring leaf phenology. We suggest that P. tremuloides demonstrated a discrepancy between the ecological optimum and the physiological optimum minimum winter temperature. The sub‐optimal growing condition of P. tremuloides is potentially caused by the warmer ecological optimum than the physiological optimum. Assisted migration and breeding of fast growers to reforest cooler plantation sites can improve productivity. Transferring the study populations to less than 4°C of extreme minimum temperature appears safe for reforestation aligning with the historical recolonization direction of the species. This is equivalent to a 5–10° latitudinal northward movement. Fall frost hardiness is an effective criterion for family selection in the range tested in this study.
The sub‐optimality of local Populus tremuloides demonstrated discrepancies between the ecological optimum and physiological optimum and the tree species tended to express a colder ecological optimum than the physiological optimum. Transferring the study populations (<‐4°C of extreme minimum temperature, EMT) appears safe for reforestation, equivalent to 5‐10° latitudinal northward movement.
Long‐term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a “low immunological ...risk of rejection” could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double‐blind placebo‐controlled clinical study (Eudract: 2010‐019574‐33) to analyze the benefit–risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti‐HLA immunization). The primary endpoint was improvement of renal function. Fifty‐two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti‐HLA antibodies without histological lesion (one donor‐specific antibodies DSA and one non‐DSA). Clearly, tacrolimus withdrawal must be avoided even in long‐term highly selective stable kidney recipients.
A prospective, randomized, multicenter, double‐blind, placebo‐controlled clinical study shows the failure of tacrolimus withdrawal in highly stable kidney transplant patients.
From quantum to classical by numbers Sokolovski, D; Brouard, S; Alonso, D
New journal of physics,
12/2019, Letnik:
21, Številka:
12
Journal Article
Recenzirano
Odprti dostop
We follow Kofler and Brukner (2007 Phys. Rev. Lett. 99 180403) in studying the conditions under which a classical picture emerges from the results of not too accurate quantum measurements made on ...large macroscopic objects. We show that for such objects, consisting of a large number of microscopic elements obeying quantum laws, the Central Limit theorem guarantees the existence of classical values for collective variables, even if the corresponding operators do not commute. Owing to localisation of the overall wave function in any chosen representation, these values can be measured to a small relative error without significantly altering the state of the object. We study a simple model, which includes a rudimentary observer capable of detecting in the coordinate space the position of a macroscopic pointer. The pointer can be employed to measure such quantities, not directly accessible to the observer, as linear or angular momenta. A purely classical picture arises provided the measurements are made on macroscopic objects. Results of measurements, made on small quantum objects, cannot be predicted with certainty, but acquire certain objectivity when encoded in macroscopic pointers' positions accessible to all observers. Our estimates show that the classical conditions could, in principle, be realised for systems with number of constituent parts of the order of the Avogadro constant. It is possible that the approach captures the essential features of the quantum-to-classical behaviour, although its extension to more realistic systems is likely to be required.
Background
Exposure to respiratory allergens triggers airway hyperresponsiveness and inflammation characterized by the expansion of TH2 cells and the production of allergen specific IgE. Allergic ...asthma is characterized by an alteration in immune regulatory mechanisms leading to an imbalance between pro‐ and anti‐inflammatory components of the immune system.
Aims
Recently B cells have been described as central regulators of exacerbated inflammation, notably in the case of autoimmunity. However, to what extent these cells can regulate airway inflammation and asthma remains to be elucidated.
Materials & Methods
We took advantage of a allergic asthma model in mice induced by percutaneous sensitization and respiratory challenge with an extract of house dust mite.
Results
In this study, we showed that the induction of allergic asthma alters the homeostasis of IL‐10+ Bregs and favors the production of inflammatory cytokines by B cells. Deeper transcriptomic and phenotypic analysis of Bregs revealed that they were enriched in a CD9+ B cell subset. In asthmatic mice the adoptive transfer of CD9+ B cells normalized airway inflammation and lung function by inhibiting TH2‐ and TH17‐driven inflammation in an IL‐10‐dependent manner, restoring a favorable immunological balance in lung tissues. Indeed we further showed that injection of CD9+ Bregs controls the expansion of lung effector T cells allowing the establishment of a favorable regulatory T cells/effector T cells ratio in lungs.
Conclusion
This finding strengthens the potential for Breg‐targeted therapies in allergic asthma.
In response to the article by Boardman et al (page 931), the authors provide a brief update on chimeric antigen receptor technology, particularly regarding regulatory T cells in the context of ...transplantation.
The contribution of regulatory T cells in the maintenance of kidney graft survival is of major interest. Although many experimental models suggest a role in the induction of graft tolerance, ...reproducing these findings in clinic is less clear. While modulation of the regulatory T cell response is a promising therapeutic concept in transplantation, a better understanding of function, phenotype and biology is needed to be able to optimally exploit these cells in order to induce graft tolerance. With this in mind, we review here the current understanding of the phenotypic‐functional delineation of Tregs and how Tregs can contribute to graft survival. We highlight their potential role in long‐term graft survival and kidney operational tolerance. We also discuss the mechanisms needed for the molecular development of regulatory T cells: A combination of FOXP3 molecular partners, epigenetic, metabolic, and posttranslational modifications are necessary to generate well‐functioning regulatory T cells and maintain their core identify. We discuss how an improved understanding of these mechanisms will permit the identification of new potent therapeutic strategies to improve kidney graft survival.
In this review, the authors summarize and discuss human regulatory T cells' role in long‐term graft survival, new data regarding molecular pathways guiding the development, plasticity and stability of regulatory T cells, and how exploiting these mechanisms could be a potent therapeutic strategy to induce transplantation tolerance.
Aspen (Populus tremuloides Michx) is a widespread commercial forest tree of high economic importance in western Canada and has been subject to tree improvement efforts over the past two decades. Such ...improvement programs rely on accurate estimates of the genetic gain in growth traits and correlated response in adaptive traits that are important for forest health. Here, we estimated genetic parameters in 10 progeny trials containing >30,000 trees with pedigree structures based on a partial factorial mating design that includes 60 half-sibs, 100 full-sib families and 1,400 clonally replicated genotypes. Estimated narrow-sense and broad-sense heritabilities were low for height and diameter (~0.2), but moderate for the dates of budbreak and leaf senescence (~0.4). Furthermore, estimated genetic correlations between growth and phenology were moderate to strong with tall trees being associated with early budbreak (r = -0.3) and late leaf senescence (r = -0.7). Survival was not compromised, but was positively associated with early budbreak or late leaf senescence, indicating that utilizing the growing season was more important for survival and growth than avoiding early fall or late spring frosts. These result suggests that populations are adapted to colder climate conditions and lag behind environmental conditions to which they are optimally adapted due to substantial climate warming observed over the last several decades for the study area.
Operationally tolerant patients (TOL) display a higher number of blood B cells and transcriptional B cell signature. As they rarely develop an allo‐immune response, they could display an abnormal B ...cell differentiation. We used an in vitro culture system to explore T‐dependent differentiation of B cells into plasma cells. B cell phenotype, apoptosis, proliferation, cytokine, immunoglobulin production and markers of differentiation were followed in blood of these patients. Tolerant recipients show a higher frequency of CD20+CD24hiCD38hi transitional and CD20+CD38loCD24lo naïve B cells compared to patients with stable graft function, correlating with a decreased frequency of CD20−CD38+CD138+ differentiated plasma cells, suggestive of abnormal B cell differentiation. B cells from TOL proliferate normally but produce more IL‐10. In addition, B cells from tolerant recipients exhibit a defective expression of factors of the end step of differentiation into plasma cells and show a higher propensity for cell death apoptosis compared to patients with stable graft function. This in vitro profile is consistent with down‐regulation of B cell differentiation genes and anti‐apoptotic B cell genes in these patients in vivo. These data suggest that a balance between B cells producing IL‐10 and a deficiency in plasma cells may encourage an environment favorable to the tolerance maintenance.
B cells from tolerant recipients do not fully terminally differentiate into plasma cells in vitro and show a higher propensity for apoptosis compared to B cells from stable patients on immunosuppression.
The angiotensin II type 1 receptor (AT1R) is an emerging target of functional non‐HLA antibodies (Ab). We examined the potential of determining the degree of presensitization against AT1R as a risk ...factor for graft survival and acute rejection (AR). The study included 599 kidney recipients between 1998 and 2007. Serum samples were analyzed in a blinded fashion for anti‐AT1R antibodies (AT1R‐Abs) using a quantitative solid‐phase assay. A threshold of AT1R‐Ab levels was statistically determined at 10 U based on the time to graft failure. An extended Cox model determined risk factors for occurrence of graft failure and a first AR episode. AT1R‐Abs >10 U were detected in 283 patients (47.2%) before transplantation. Patients who had a level of AT1R‐Abs >10 U had a 2.6‐fold higher risk of graft failure from 3 years posttransplantation onwards (p = 0.0005) and a 1.9‐fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p = 0.0393). Antibody‐mediated rejection (AMR) accounted for 1/3 of AR, whereby 71.4% of them were associated with >10 U of pretransplant AT1R‐Abs. Pretransplant anti‐AT1R‐Abs are an independent risk factor for long‐term graft loss in association with a higher risk of early AR episodes.
The authors find that a high serum level of anti‐angiotensin II type 1 receptor antibodies in kidney transplant recipients before transplantation is an independent risk factor for long‐term graft loss in association with a higher risk of early acute rejection episodes. See related paper by Taniguchi et al (page 2577) and editorial by Tinckam and Campbell (page 2515).
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