Operational Tolerance Research Articles

Multiscale Understanding of Surface Structural Effects on High-Temperature Operational Resiliency of Layered Oxide Cathodes.

The worldwide energy demand in electric vehicles and the increasing global temperature have called for development of high-energy and long-life lithium-ion batteries (LIBs) with improved high-temperature operational resiliency. However, current attention has been mostly focused on cycling aging at elevated temperature, leaving considerable gaps of knowledge in the failure mechanism, and practical control of abusive calendar aging and thermal runaway that are highly related to the eventual operational lifetime and safety performance of LIBs. Herein, using a combination of various in situ synchrotron X-ray and electron microscopy techniques, a multiscale understanding of surface structure effects involved in regulating the high-temperature operational tolerance of polycrystalline Ni-rich layered cathodes is reported. The results collectively show that an ultraconformal poly(3,4-ethylenedioxythiophene) coating can effectively prevent a LiNi0.8 Co0.1 Mn0.1 O2 cathode from undergoing undesired phase transformation and transition metal dissolution on the surface, atomic displacement, and dislocations within primary particles, intergranular cracking along the grain boundaries within secondary particles, and intensive bulk oxygen release during high state-of-charge and high-temperature aging. The present work highlights the essential role of surface structure controls in overcoming the multiscale degradation pathways of high-energy battery materials at extreme temperature.

Self-Centered Function of Adaptive Immunity in Regulation of Immune Responses and in Tolerance.

The search for common mechanisms underlying the pathogenesis of chronic inflammatory conditions has crystalized the concept of continuous dual resetting of the immune repertoire (CDR) as a basic principle of the immune system function. Consequently, outlined was the first dynamic comprehensive picture of the immune system function. The goal of this study is to elaborate on regulation of immune responses and mechanisms of tolerance, particularly focusing on adaptive immunity. It is well established that the T/B cell repertoire is selected and maintained based on interactions with self. However, their activation also requires interaction with a self-specific major histocompatibility complex (MHC) “code,” i.e., the context of MHC molecules. Therefore, not only repertoire selection and maintenance but also the T/B cell activation and function are self-centered. Thus, adaptive effectors may be primarily focused on the state of self and maintenance of integrity of the self, and only to a certain degree on elimination of the foreign. As examples of such function are used immunologically poorly understood MHC-disparate settings typical for transplantation and pregnancy. Transplantation represents an extreme setting of strong systemic compartment-level adaptive/MHC-restricted immune responses. Described are clinically identified conditions for operational tolerance of MHC-disparate tissues/living systems in allotransplantation, which are in line with the CDR-proposed self-centered regulatory role of T/B cells. In contrast, normal pregnancy is coexistence of semiallogeneic or entirely allogeneic mother and fetus, but without alloreactivity akin to transplantation settings. Presented data support the notion that maintenance of pregnancy is a process that relies predominantly on innate/MHC-independent immune mechanisms. By the inception of hemotrophic stage of pregnancy (second and third trimester), both mother and child are individual living systems, with established adaptive immune repertoires. Although mother-fetus interactions at that point become indirect systemic compartment-level communications, their interactions throughout gestation remain within the innate realm of molecular-level adaptations.

Operation tolerance after liver transplantation

Kyeong Deok Kim, Gyu-Seong Choi, Sunghae Park, Young Ju Oh, Sang Oh Yun, Manuel Lim, Eun Sung Jeong, Ji Eun Kwon, Jaehun Yang, Jinsoo Rhu, Jong Man Kim, Jae-Won Joh. Korean J Transplant 2021;35:131. https://doi.org/10.4285/ATW2021.PO-1257

Cellular and genetic signatures of operational tolerance in kidney transplant recipients through single cell RNA sequencing analysis

Cellular and genetic signatures of operational tolerance in kidney transplant recipients through single cell RNA sequencing analysis

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review

Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW.

The Balance Between Memory and Regulatory Cell Populations in Kidney Transplant Recipients with Operational Tolerance

The Balance Between Memory and Regulatory Cell Populations in Kidney Transplant Recipients with Operational Tolerance

Anti-Donor Regulatory T-Cell Therapy in Adult-to-Adult Living Donor Liver Transplantation: A Case Report

We report on the case of a 50-year-old female patient with symptomatic polycystic liver disease who underwent living donor liver transplantation (LDLT) using right liver graft from her ABO-identical husband. To achieve operational tolerance, regulatory T-cell (T-reg)-based cell therapy was applied, following the protocol introduced by Todo et al. Briefly, donor lymphocytes were collected by leukapheresis 20 days before LDLT without any adverse events, and the cells were irradiated with a dose of 30 Gy and kept frozen. Lymphopheresis of the recipient was conducted in a similar manner 1 day before LDLT, and donor cells and recipient cells were cultured with anti-CD80/86 antibodies to induce the donor-specific T-reg. At 14 days of culture, the CD4+CD25+Foxp3+ cells had increased from 1.51% to 5.21%, and mixed lymphocyte reaction assay using an intracellular fluorescent dye carboxyfluorescein diacetate succinimidyl ester-labeling technique revealed donor-specific hyporesponsiveness of CD4-positive lymphocytes. On postoperative day (POD) 13 (14 days of culture), these cells were infused to the recipient intravenously without any adverse events. Initial immunosuppression consisted of tacrolimus, steroid and mycophenolate mofetil (MMF), and cyclophosphamide (40 mg/kg) administered on POD 5. Both the steroid and MMF were continued until 4 weeks after LDLT, and the patient was discharged on POD 30 with normal liver function. On POD 52, the patient developed acute cellular rejection and received appropriate reinforcement of immunosuppressive therapy and is currently doing well with normal liver function 30 months after LDLT with reduced anti-donor allo-activity. In summary, T-reg therapy was safely performed in adult LDLT, and we are following the patient carefully to determine whether she can achieve operational tolerance in the future.

Reaching beyond the sulfided surface: Doping of copper cation to expand the pH tolerance range for SZVI

Sulfidation of zero-valent iron (SZVI) is an important means to greatly inhibit the formation of inert hydr/oxide and improve the overall reactivity in pollutant removal reactions, which is mainly benefiting from the formation of FeSx layer on surface of the zero-valent iron (ZVI). However, FeSx phase can act as reducing reagent in the treatment of pollutants, resulting in inevitable consumption. Considering that, copper cation was introduced to the FeSx phases to prepare copper-doped sulfides with improved durability. In this study, we successfully prepared copper-doped SZVI (Cu-SZVI). The composition and structure have been clearly confirmed by a combination of several techniques, including Raman spectroscopy and X-ray powder diffraction. Cu-SZVI exhibits a superior sequestration reaction to remove Cr(VI) with higher removal capacity of 82.93 mg/g, with the comparison of SZVI (57.54 mg/g) and ZVI (8.23 mg/g). Moreover, Cu-SZVI possesses better operational pH tolerance and longer lifetime of usage, which makes it particularly attractive to large-scale environmental applications. This work proposes a new way to modify SZVI by doping a secondary cation, which can be used to further explore new SZVI materials based on specific needs.

Defining a Methylation Signature Associated With Operational Tolerance in Kidney Transplant Recipients.

Operational tolerance after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. We performed genome-wide analysis of DNA methylation in peripheral blood mononuclear cells from kidney transplant recipients with chronic rejection and operational tolerance from the Genetic Analysis of Molecular Biomarkers of Immunological Tolerance (GAMBIT) study. Our results showed that both clinical stages diverge in 2737 genes, indicating that each one has a specific methylation signature associated with transplant outcome. We also observed that tolerance is associated with demethylation in genes involved in immune function, including B and T cell activation and Th17 differentiation, while in chronic rejection it is associated with intracellular signaling and ubiquitination pathways. Using co-expression network analysis, we selected 12 genomic regions that are specifically hypomethylated or hypermethylated in tolerant patients. Analysis of these genes in transplanted patients with low dose of steroids showed that these have a similar methylation signature to that of tolerant recipients. Overall, these results demonstrate that methylation analysis can mirror the immune status associated with transplant outcome and provides a starting point for understanding the epigenetic mechanisms associated with tolerance.

High-Performance and Compact Silicon Photonic 3-dB Adiabatic Coupler Based on Shortest Mode Transformer Method

A 2 × 2 3-dB coupler is one of the essential photonic components, as a building block of Mach-Zehnder interferometers, to realize large-scale photonic integrated circuits. Unlike typical 2 × 2 3-dB couplers based on direction couplers or multimode interference couplers, adiabatic couplers offer various advantages such as broadband operation and superior fabrication tolerance thanks to their unique operating mechanism of adiabatic mode evolution. However, an adiabatic coupler typically requires a long device length for ideal adiabatic operation without the excitations of unwanted modes. Here, we report on a compact 2 × 2 3-dB adiabatic coupler designed using the shortest mode transformer method. By optimizing the profile of the waveguide widths and the gap spacing, the compact 3-dB coupler was designed with a short coupling length of 23.2 μm. The fabricated device exhibits a 3-dB splitting ratio with less than ± 0.3 dB power oscillation and a low excess loss of 0.23 dB over a broad wavelength range of 1485–1620 nm. To the best of our knowledge, our coupler has the shortest length among the adiabatic couplers with a minimum feature size of 200 nm, reported to date.

Intranodal Sirolimus Induces Regulatory T Cells in Human Hepatic Lymph Nodes via Interleukin 10 Signaling.

Intranodal Sirolimus Induces Regulatory T Cells in Human Hepatic Lymph Nodes via Interleukin 10 Signaling.

Activated CD4+ T Cells and Highly Differentiated Alloreactive CD4+ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients.

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation‐induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third‐party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor‐specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.

Multi-controlled broadband terahertz absorber engineered with VO2-integrated borophene metamaterials

We demonstrated a dynamically controlled broadband terahertz (THz) metamaterials absorber, which composed of continuous vanadium dioxide (VO2) film, a silicon dioxide (SiO2) layer, and a structured borophene layer. When VO2 is in its metallic state and the armchair direction of borophene along x axis, the proposed absorber realizes an absorptivity peak value of 100% at 7.2 THz for y polarized normal incidence, and an absorptivity peak value of 79% at 8.9 THz for x polarized normal incidence. It is the anisotropic property of borophene that results in the absorptivity difference for x and y polarization in the whole frequency range. Simulated electric field distribution and surface current oscillation has been extracted to explain the physical mechanism of THz wave absorption. Through modifying the geometric parameters of metamaterials microstructure, the broadband absorption performance can be tailored passively. Additionally, the proposed metamaterials absorber has been actively controlled by manipulating the carrier density of borophene and the conductivity of VO2, respectively. The absorptivity can be switched from 45% to 100% at 7.2 THz by changing the carrier density of borophene, and from 22% to 100% at 7.2 THz by changing the conductivity of VO2. Moreover, the proposed absorber exhibits an excellent operation tolerance for oblique TE and TE polarized incidence from 0° to 60°. This work provides a novel approach to design dynamically controlled broadband THz absorbers, which reveals promising applications in the devices of optoelectronic switches, cloakings, filters, and sensors, etc.

Cobalt/nitrogen doped porous carbon as catalysts for efficient oxygen reduction reaction: Towards hybrid enzymatic biofuel cells

Electrochemical oxygen reduction reaction (ORR) represents a crucial cathodic process of different fuel cells. The development of highly active and stable noble metal-free ORR electrocatalysts remains as one of major challenges. Herein, we report cobalt/nitrogen co-doped porous carbon materials (Co-N-C) originated from well-designed bimetal-organic frameworks (Zn100-xCox-ZIF) as efficient ORR electrocatalysts in both pH-neutral and alkaline solutions. The compositional and structural features, and the corresponding ORR activity can be tailored by tuning the Zn/Co ratio in the precursor. Remarkable features of large surface-area and suitable graphitization degree and well-dispersed Co-N-C moieties, enable a high catalytic efficiency. The optimized electrocatalyst registers considerable ORR performance with a high half-wave potential of 0.65 V vs RHE and a saturated current density of 5.30 mA cm−2 close to the value of the commercial Pt/C in 0.1 M pH 7.0 PBS, along with considerable operational stability and tolerance to glucose. A preliminary one-compartment hybrid glucose/O2 enzymatic biofuel cell, consisting of the Co-N-C-10 abiotic cathode and a glucose oxidizing bioanode, is constructed and tested. Furthermore, Co-N-C presents reasonable ORR electrocatalytic activity and operational stability in alkaline condition.

Advances in Fault Diagnostics and Post‐Fault Operation of Electrical Drives

Advances in Fault Diagnostics and Post‐Fault Operation of Electrical Drives

TCL1A, B Cell Regulation and Tolerance in Renal Transplantation.

Despite much progress in the management of kidney transplantation, the need for life-long immunosuppressive therapies remains a major issue representing many risks for patients. Operational tolerance, defined as allograft acceptance without immunosuppression, has logically been subject to many investigations with the aim of a better understanding of post-transplantation mechanisms and potentially how it would be induced in patients. Among proposed biomarkers, T-cell Leukemia/Lymphoma protein 1A (TCL1A) has been observed as overexpressed in the peripheral blood of operational tolerant patients in several studies. TCL1A expression is restricted to early B cells, also increased in the blood of tolerant patients, and showing regulatory properties, notably through IL-10 secretion for some subsets. TCL1A has first been identified as an oncogene, overexpression of which is associated to the development of T and B cell cancer. TCL1A acts as a coactivator of the serine threonine kinase Akt and through other interactions favoring cell survival, growth, and proliferation. It has also been identified as interacting with others major actors involved in B cells differentiation and regulation, including IL-10 production. Herein, we reviewed known interactions and functions of TCL1A in B cells which could involve its potential role in the set up and maintenance of renal allograft tolerance.

Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance. Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection, and cryopreserved. Immunoablation using busulfan, cyclophosphamide, and rabbit antithymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic, and clinical evidence of rejection while off immunosuppression at 2 y post-aHSCT. Two of the 5 patients achieved operational tolerance with no clinical or histologic evidence of PSC progression or allorejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now >3 y after aHSCT. A fourth patient was weaned off immunosuppression but died 212 d after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T-cell clones, loss of autoantibodies, and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors. Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed render this specific protocol unsuitable for clinical adoption.

Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation.

Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.

Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management.

Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1year after stopping immunosuppression. Among 88 subjects (median age 11years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n=32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n=32) and/or tacrolimus (n=38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4years for either tolerant or nontolerant subjects. Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

Investigation of the fake reject cases with unqualified operational dimension based on the error compensation and tolerance compression

A fake reject (FR) with unqualified operational dimension often occurs during part machining when the operational data do not coincide with the design data, which can lead to unnecessary waste. We investigated novel judgment and remedial measures for FR to enhance the product qualification rate. We first discuss the reasons for FRs that occur when the calculation for the operational tolerance of the dimension chain is too narrow when calculated using the worst-case scenario method for the process. Following that, we present a novel method for estimating FRs by calculating a new dimension chain. The operational dimension is treated as the concluding link. The actual deviations of the dimensions generated before the operational dimension are used to replace their upper and lower deviations. Finally, based on the error compensation relationship among the component links in the process dimension chain, we propose a novel remedial measure for FR via compressing the dimension tolerance in subsequent processing. We also calculated the dimension tolerance after tolerance compression. This results from this study contribute to the assessment and processing of FRs in part machining.