Donor and recipient leukocytes in organ allografts of recipients with variable donor-specific tolerance: With particular reference to chronic rejection

We have attributed organ engraftment to clonal exhaustion-deletion of host-versus-graft and graft-versus-host reactions that are reciprocally induced and governed by migratory donor and recipient leukocytes. The so-called donor passenger leukocytes that migrate from the allograft into the recipients have been thoroughly studied (chimerism), but not the donor leukocytes that remain in, or return to, the transplanted organ. Therefore, using flow cytometry we determined the percentage and lineages of donor leukocytes in cell suspensions prepared from Lewis (LEW) cardiac allografts to 100 days posttransplantation. The LEW hearts were transplanted to naive untreated Brown Norway (BN) recipients (group 2), to naive BN recipients treated with a 28-day or continuous course of tacrolimus (TAC) (groups 3 and 4), and to drug-free BN recipients pretolerized by earlier bone marrow cell (BMC) or orthotopic LEW liver transplantation (groups 5 and 6). The findings in the heart cell suspensions were correlated with the results from parallel histopathologic-immunocytochemical studies and other studies of the grafts and of host tissues. Although the LEW heart allografts were rejected in 9.6 days by the unmodified recipients of group 2, all beat for 100 days in the recipients of groups 3 through 6. Nevertheless, all of the long-surviving cardiac allografts (but not the isografts in group 1) were the targets of an immune reaction at 5 days, reflected by dramatic increases in the ratio of leukocytes to nonleukocyte nucleated cells from normal values of 1:5-1:6 to 1:1-5:1 and by manifold other evidence of a major inflammatory event. The acute changes returned to baseline by 100 days in the chronic rejection (CR) free hearts of groups 4 and 6, but not in the CR-afflicted hearts of short-course TAC group 3 or the less-severely damaged hearts of the BMC-prime group 5. The freedom from CR in groups 4 and 6 was associated with a large donor contribution to the intracardiac leukocyte population at 5 days (28.6% and 22% in the respective groups) and at 100 days (30.5% in group 4 and 8.4% in group 6) compared with 2% and 1.2% at 100 days in the CR-blighted allografts of the partially tolerant animals of groups 3 and 5. Whether large or small, the donor leukocyte fraction always included a subset of class II leukocytes that had histopathologic features of dendritic cells. These class II+ cells were of mixed myeloid (CD11-b/c+) and lymphoid lineages; their migration was markedly inhibited by TAC and accelerated by donor-specific priming and TAC discontinuance. Although a large donor leukocyte population and a normal leukocyte/nonleukocyte cell ratio were associated with freedom from CR, these findings and the lineage profile of the intracardiac leukocytes were not associated with tolerance in the animals of groups 3 and 4 under active TAC treatment. The findings in this study, singly and in their entirety, are compatible with our previously proposed leukocyte migration-localization paradigm of organ allograft acceptance and tolerance

Hypophosphorylation of the architectural chromatin protein DEK in death-receptor-induced apoptosis revealed by the isotope coded protein label proteomic platform

During apoptosis nuclear morphology changes dramatically due to alterations of chromatin architecture and cleavage of structural nuclear proteins. To characterize early events in apoptotic nuclear dismantling we have performed a proteomic study of apoptotic nuclei. To this end we have combined a cell-free apoptosis system with a proteomic platform based on the differential isotopic labeling of primary amines with N -nicotinoyloxy-succinimide. We exploited the ability of this system to produce nuclei arrested at different stages of apoptosis to analyze proteome alterations which occur prior to or at a low level of caspase activation. We show that the majority of proteins affected at the onset of apoptosis are involved in chromatin architecture and RNA metabolism. Among them is DEK, an architectural chromatin protein which is linked to autoimmune disorders. The proteomic analysis points to the occurrence of multiple PTMs in early apoptotic nuclei. This is confirmed by showing that the level of phosphorylation of DEK is decreased following apoptosis induction. These results suggest the unexpected existence of an early crosstalk between cytoplasm and nucleus during apoptosis. They further establish a previously unrecognized link between DEK and cell death, which will prove useful in the elucidation of the physiological function of this protein.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55852/1/5758_ftp.pd

C-reactive protein for diagnosing late-onset infection in newborn infants

BACKGROUND: Late-onset infection is the most common serious complication associated with hospital care for newborn infants. Because confirming the diagnosis by microbiological culture typically takes 24 to 48 hours, the serum level of the inflammatory marker C-reactive protein (CRP) measured as part of the initial investigation is used as an adjunctive rapid test to guide management in infants with suspected late-onset infection. OBJECTIVES: To determine the diagnostic accuracy of serum CRP measurement in detecting late-onset infection in newborn infants. SEARCH METHODS: We searched electronic databases (MEDLINE, Embase, and Science Citation Index to September 2017), conference proceedings, previous reviews, and the reference lists of retrieved articles. SELECTION CRITERIA: We included cohort and cross-sectional studies evaluating the diagnostic accuracy of serum CRP levels for the detection of late-onset infection (occurring more than 72 hours after birth) in newborn infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility for inclusion, evaluated the methodological quality of included studies, and extracted data to estimate diagnostic accuracy using hierarchical summary receiver operating characteristic (SROC) models. We assessed heterogeneity by examining variability of study estimates and overlap of the 95% confidence interval (CI) in forest plots of sensitivity and specificity. MAIN RESULTS: The search identified 20 studies (1615 infants). Most were small, single-centre, prospective cohort studies conducted in neonatal units in high- or middle-income countries since the late 1990s. Risk of bias in the included studies was generally low with independent assessment of index and reference tests. Most studies used a prespecified serum CRP threshold level as the definition of a 'positive' index test (typical cut-off level between 5 mg/L and 10 mg/L) and the culture of a pathogenic micro-organism from blood as the reference standard.At median specificity (0.74), sensitivity was 0.62 (95% CI 0.50 to 0.73). Heterogeneity was evident in the forest plots but it was not possible to conduct subgroup or meta-regression analyses by gestational ages, types of infection, or types of infecting micro-organism. Covariates for whether studies used a predefined threshold or not, and whether studies used a standard threshold of between 5 mg/L and 10 mg/L, were not statistically significant. AUTHORS' CONCLUSIONS: The serum CRP level at initial evaluation of an infant with suspected late-onset infection is unlikely to be considered sufficiently accurate to aid early diagnosis or select infants to undergo further investigation or treatment with antimicrobial therapy or other interventions

Killing of Targets by CD8+ T Cells in the Mouse Spleen Follows the Law of Mass Action

It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response

The ROS Scavenger, NAC, Regulates Hepatic Vα14iNKT Cells Signaling during Fas mAb-Dependent Fulminant Liver Failure

Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18−/− mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses

Combination of searches for heavy spin-1 resonances using 139 fb−1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, , and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion

Adaptation and psychometric evaluation of the Chinese version of the functional assessment of chronic illness therapy spiritual well-being scale among Chinese childhood cancer patients in China

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