Transplant rejection and risk: in search of the genetic dark matter.
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ABSTRACT:
SUBMITTER: Oetting WS
PROVIDER: S-EPMC4105001 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient's circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non-HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.
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Project description:Ultralight bosons such as axion-like particles are viable candidates for dark matter. They can form stable, macroscopic field configurations in the form of topological defects that could concentrate the dark matter density into many distinct, compact spatial regions that are small compared with the Galaxy but much larger than the Earth. Here we report the results of the search for transient signals from the domain walls of axion-like particles by using the global network of optical magnetometers for exotic (GNOME) physics searches. We search the data, consisting of correlated measurements from optical atomic magnetometers located in laboratories all over the world, for patterns of signals propagating through the network consistent with domain walls. The analysis of these data from a continuous month-long operation of GNOME finds no statistically significant signals, thus placing experimental constraints on such dark matter scenarios.
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Project description:AimsThis study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR).MethodsAdult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model.ResultsFourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%).ConclusionsTransplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.
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Project description:Cosmological observations indicate that dark matter makes up 85% of all matter in the universe yet its microscopic composition remains a mystery. Dark matter could arise from ultralight quantum fields that form macroscopic objects. Here we use the global positioning system as a ~?50,000?km aperture dark matter detector to search for such objects in the form of domain walls. Global positioning system navigation relies on precision timing signals furnished by atomic clocks. As the Earth moves through the galactic dark matter halo, interactions with domain walls could cause a sequence of atomic clock perturbations that propagate through the satellite constellation at galactic velocities ~?300?km?s-1. Mining 16 years of archival data, we find no evidence for domain walls at our current sensitivity level. This improves the limits on certain quadratic scalar couplings of domain wall dark matter to standard model particles by several orders of magnitude.
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Project description:The presence of interstitial pneumonitis (IP) on surveillance lung biopsy specimens in lung transplant recipients is poorly described, and its impact on posttransplant outcomes is not established. The following study assessed the association of posttransplant IP with the development of bronchiolitis obliterans syndrome (BOS).We examined all recipients of primary cadaveric lung transplants at our institution between January 1, 2000, and December 31, 2007 (N = 145). Patients had bronchoscopies with BAL, and transbronchial biopsies performed for surveillance during posttransplant months 1, 3, 6, and 12 as well as when clinically indicated. Patients were given a diagnosis of IP if, in the absence of active infection and organizing pneumonia, they showed evidence of interstitial inflammation and fibrosis on two or more biopsy specimens.IP was a significant predictor of BOS (OR, 7.84; 95% CI, 2.84-21.67; P < .0001) and was significantly associated with time to development of BOS (hazard ratio, 3.8; 95% CI, 1.93-7.39; P = .0001) within the first 6 years posttransplant. The presence of IP did not correlate with a significantly higher risk of mortality or time to death. There was no association between the presence of IP and the development of or time to acute rejection.The presence of IP on lung transplant biopsy specimens suggests an increased risk for BOS, which is independent of the presence of acute cellular rejection.
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Project description:Ultra-low-radioactive titanium is the main perspective material for cryostat fabrication in dark matter search experiments. The pathways of the uranium and thorium contamination of Ti sponges produced by the Kroll process were analyzed. The general role of Mg in Ti sponge contamination by U and Th was established. It was found that when transformed to MgCl2 in the Kroll process, Mg was purified from U and Th, and further MgCl2 reduction and sublimation makes it possible to produce low-radioactive Ti sponges.
| S-EPMC9786686 | biostudies-literature
Project description:Studying immune repertoire in the context of organ transplant provides important information on how adaptive immunity may contribute and modulate graft rejection. Here we characterize the peripheral blood immune repertoire of individuals before and after kidney transplant using B cell receptor sequencing in a longitudinal clinical study. Individuals who develop rejection after transplantation have a more diverse immune repertoire before transplant, suggesting a predisposition for post-transplant rejection risk. Additionally, over 2 years of follow-up, patients who develop rejection demonstrate a specific set of expanded clones that persist after the rejection. While there is an overall reduction of peripheral B cell diversity, likely due to increased general immunosuppression exposure in this cohort, the detection of specific IGHV gene usage across all rejecting patients supports that a common pool of immunogenic antigens may drive post-transplant rejection. Our findings may have clinical implications for the prediction and clinical management of kidney transplant rejection.
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Project description: Not available
| S-EPMC8596849 | biostudies-literature
Project description:We examine the dark matter phenomenology of a composite electroweak singlet state. This singlet belongs to the Goldstone sector of a well-motivated extension of the Littlest Higgs with T-parity. A viable parameter space, consistent with the observed dark matter relic abundance as well as with the various collider, electroweak precision and dark matter direct detection experimental constraints is found for this scenario. T-parity implies a rich LHC phenomenology, which forms an interesting interplay between conventional natural SUSY type of signals involving third generation quarks and missing energy, from stop-like particle production and decay, and composite Higgs type of signals involving third generation quarks associated with Higgs and electroweak gauge boson, from vector-like top-partners production and decay. The composite features of the dark matter phenomenology allows the composite singlet to produce the correct relic abundance while interacting weakly with the Higgs via the usual Higgs portal coupling [Formula: see text], thus evading direct detection.
| S-EPMC5799589 | biostudies-other
Project description:Background and purposeWhite matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsHeritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.ResultsA total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.ConclusionsCommon genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
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