Cell-based therapy with natural (CD4(+)CD25(hi)CD127(lo)) regulatory T cells to induce transplant tolerance is now technically feasible. However, regulatory T cells from hemodialysis patients ...awaiting transplantation may be functionally/numerically defective. Human regulatory T cells are also heterogeneous, and some are able to convert to proinflammatory Th17 cells. This study addresses the suitability of regulatory T cells from hemodialysis patients for cell-based therapy in preparation for the first clinical trials in renal transplant recipients (the ONE Study).
Healthy controls and age- and sex-matched hemodialysis patients without recent illness/autoimmune disease on established, complication-free hemodialysis for a minimum of 6 months were recruited. Circulating regulatory T cells were studied by flow cytometry to compare the regulatory T cell subpopulations. Regulatory T cells from members of each group were compared for suppressive function and plasticity (IL-17-producing capacity) before and after in vitro expansion with and without Rapamycin, using standard assays.
Both groups had similar total regulatory T cells and subpopulations I and III. In each subpopulation, regulatory T cells expressed similar levels of the function-associated markers CD27, CD39, HLA-DR, and FOXP3. Hemodialysis regulatory T cells were less suppressive, expanded poorly compared with healthy control regulatory T cells, and produced IL-17 in the absence of Rapamycin. However, Rapamycin efficiently expanded hemodialysis regulatory T cells to a functional and stable cell product.
Rapamycin-based expansion protocols should enable clinical trials of cell-based immunotherapy for the induction of tolerance to renal allografts using hemodialysis regulatory T cells.
ObjectivesTo advance understanding of how message framing can be used to maximise public support across different pricing policies for alcohol, tobacco and sugary drinks/foods that prevent ...consumption of cancer-causing products.DesignWe designed a 3×4×3 randomised factorial experiment to test responses to messages with three pricing policies, four message frames and three products.SettingOnline survey panel (Qualtrics) in 2019.ParticipantsAdults (N=1850) from the UK and USA.InterventionsParticipants randomly viewed one of 36 separate messages that varied by pricing policy (increasing taxes, getting rid of price discounts, getting rid of low-cost products), four frames and product (alcohol, tobacco, sugary drinks/foods).Primary and secondary outcome measuresWe assessed the relationship between the message characteristics and four dependent variables. Three were related to policy support: (1) increasing taxes on the product mentioned in the message, (2) getting rid of price discounts and special offers on the product mentioned in the message and (3) getting rid of low-cost versions of the product mentioned in the message. One was related to reactance, a psychological response to having one’s freedom limited.ResultsWe found no effect for pricing policy in the message. Frames regarding children and reducing cancer risk moderated some outcomes, showing promise for real-world use. We found differences in support by product and reactance with greatest support and least reactance for tobacco policies, less support and more reactance for alcohol policies, and the least support and most reactance for sugary drinks/foods policies.ConclusionsCancer prevention efforts using policy interventions can be informed by the message framing literature. Our results offer insights for cancer prevention advocacy efforts across the UK and USA and highlight that tax versus non-tax approaches to increasing the cost of cancer-causing products result in similar responses from consumers.
Abstract
Background
Improvement in long-term renal allograft survival is impeded by incomplete or erroneous coding of causes of allograft loss. This study reports 13-year trends in causes of graft ...failure across the UK.
Methods
National Health Service Blood and Transplant (NHSBT) and UK Renal Registry data were linked to describe UK kidney patients transplanted in 2000–13. NHSBT graft failure categories were used, with ‘other’ recoded when free text was available. Adjusted analyses examined the influence of age, ethnicity and donor type on causes of graft failure.
Results
In 22 730 recipients, 5389 (23.7%) grafts failed within a median follow-up of 5 years. The two most frequent causes were death with a functioning graft (40.8%) and alloimmune pathology (25.0%). Graft survival was higher in recipients who were younger (mean 47.3 versus 50.7 years), received a pre-emptive transplant (20.2% versus 10.4%), spent less time on dialysis (median 1.6 versus 2.4 years) and received a living donor transplant (36.3% versus 22.2%), with no differences by sex, ethnicity or human leucocyte antigen mismatch. Allograft failure within 2 years of transplantation fell from 12.5% (2000–4) to 9.8% (2009–13). Surgical- and alloimmune-related failures decreased over time while death with a functioning graft became more common. Age, ethnicity and donor type were factors in recurrent primary disease and alloimmune pathology.
Conclusions
Since 2000 there have been reductions in surgical and alloimmune graft failures in the UK. However, graft failure codes need to be revised if they are to remain useful and effective in epidemiological and quality improvement trials.
Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, ...we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to alpha-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell-related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients.
The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and ...replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease.
In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies.
Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria.
These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum.
The theory of posttraumatic growth arose from accounts of various trauma survivors experiencing not only distress but also growth and change. An intensive care unit admission is an unplanned, sudden, ...and traumatic experience, and many survivors have posttraumatic stress that can lead to posttraumatic stress disorder. Survivors leave the intensive care unit with new functional impairments that drive depression, and they frequently experience anxiety. Amidst the stress of understanding the trauma of an intensive care unit admission, survivors can grow in their world views, relationships, and sense of self. Understanding posttraumatic growth in intensive care unit survivors will inform health care providers on how to help survivors understand their new difficulties after an intensive care unit stay and facilitate growth. This article is a conceptual review of posttraumatic growth, identifiers of posttraumatic growth, and how the tenets of the posttraumatic growth theory apply to intensive care unit survivors. Health care professionals, specifically nurses, can incorporate practices into their care during and after the intensive care unit stay that encourage understanding and positive accommodation of new difficulties brought on by the intensive care unit hospitalization to support survivor growth. Opportunities for research include incorporating posttraumatic growth assessments into post-intensive care unit clinics, self-help materials, and various programs or therapies. Outcomes associated with posttraumatic growth are listed to suggest directions for research questions concerning posttraumatic growth in intensive care unit survivors.
Insights into the role of ankyrin-1 (ANK-1) in the formation and stabilization of the red cell cytoskeleton have come from studies on the nb/nb mice, which carry hypomorphic alleles of Ank-1. Here, ...we revise several paradigms established in the nb/nb mice through analysis of an N-ethyl-N-nitrosourea (ENU)–induced Ank-1–null mouse. Mice homozygous for the Ank-1 mutation are profoundly anemic in utero and most die perinatally, indicating that Ank-1 plays a nonredundant role in erythroid development. The surviving pups exhibit features of severe hereditary spherocytosis (HS), with marked hemolysis, jaundice, compensatory extramedullary erythropoiesis, and tissue iron overload. Red cell membrane analysis reveals a complete loss of ANK-1 protein and a marked reduction in β-spectrin. As a consequence, the red cells exhibit total disruption of cytoskeletal architecture and severely altered hemorheologic properties. Heterozygous mutant mice, which have wild-type levels of ANK-1 and spectrin in their RBC membranes and normal red cell survival and ultrastructure, exhibit profound resistance to malaria, which is not due to impaired parasite entry into RBC. These findings provide novel insights into the role of Ank-1, and define an ideal model for the study of HS and malarial resistance.
Suppressor of cytokine signaling (SOCS)-2 is a member of a family of intracellular proteins implicated in the negative regulation
of cytokine signaling. The generation of SOCS-2-deficient mice, which ...grow to one and a half times the size of their wild-type
littermates, suggests that SOCS-2 may attenuate growth hormone (GH) signaling. In vitro studies indicate that, while SOCS-2 can inhibit GH action at low concentrations, at higher concentrations it may potentiate
signaling. To determine whether a similar enhancement of signaling is observed in vivo or alternatively whether increased SOCS-2 levels repress growth in vivo , we generated and analyzed transgenic mice that overexpress SOCS-2 from a human ubiquitin C promoter. These mice are not
growth-deficient and are, in fact, significantly larger than wild-type mice. The overexpressed SOCS-2 was found to bind to
endogenous GH receptors in a number of mouse organs, while phosphopeptide binding studies with recombinant SOCS-2 defined
phosphorylated tyrosine 595 on the GH receptor as the site of interaction. Together, the data implicate SOCS-2 as having dual
effects on GH signaling in vivo .
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