Acute rejection is detrimental to most transplanted solid organs, but is considered to be less of a consequence for transplanted livers. We evaluated risk factors for and outcomes after biopsy-proven ...acute rejection (BPAR) based on an analysis of a more recent national sample of recipients of liver transplants from living and deceased donors.
We analyzed data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) from 2003 through 2014 as the exploratory cohort and the Scientific Registry of Transplant Recipients (SRTR) from 2005 through 2013 as the validation cohort. We examined factors associated with time to first BPAR using multivariable Cox regression or discrete-survival analysis. Competing risks methods were used to compare causes of death and graft failure between recipients of living and deceased donors.
At least 1 BPAR episode occurred in 239 of 890 recipients in A2ALL (26.9%) and 7066 of 45,423 recipients in SRTR (15.6%). In each database, risk of rejection was significantly lower when livers came from biologically related living donors (A2ALL hazard ratio HR, 0.57; 95% confidence interval CI, 0.43-0.76; and SRTR HR, 0.78; 95% CI, 0.66-0.91) and higher in liver transplant recipients with primary biliary cirrhosis, of younger age, or with hepatitis C. In each database, BPAR was associated with significantly higher risks of graft failure and death. The risks were highest in the 12 month post-BPAR period in patients whose first episode occurred more than 1 year after liver transplantation: HRs for graft failure were 6.79 in A2ALL (95% CI, 2.64-17.45) and 4.41 in SRTR (95% CI, 3.71-5.23); HRs for death were 8.81 in A2ALL (95% CI, 3.37-23.04) and 3.94 in SRTR (95% CI, 3.22-4.83). In analyses of cause-specific mortality, associations were observed for liver-related (graft failure) causes of death but not for other causes.
Contrary to previous data, acute rejection after liver transplant is associated with significantly increased risk of graft failure, all-cause mortality, and graft failure-related death, regardless of primary liver disease etiology. Living donor liver transplantation from a biologically related donor is associated with decreased risk of rejection.
The development of human leukocyte antigen (HLA) donor‐specific antibody/antibodies (DSA) is not well described in liver transplant (LT) patients undergoing immunosuppression (IS) withdrawal ...protocols despite the allograft risk associated with de novo DSA (dnDSA). We analyzed the development of dnDSA in 69 LT patients who received calcineurin inhibitor monotherapy and were enrolled in the ITN030ST study. Of these 69 patients, 40 stable patients were randomized to IS maintenance (n = 9) or IS minimization (n = 31). Nine of the 31 IS minimization patients achieved complete withdrawal and were free of IS. Among patients who achieved stable IS monotherapy 1 year after transplantation, the prevalence of dnDSA was 18.8%. Acute rejections and the biopsy‐proven findings disqualifying patients from IS withdrawal attempt were factors associated with dnDSA development (P = 0.011 and P = 0.041, respectively). Among randomized patients, dnDSA prevalence was 51.7% after IS minimization and 66.7% in IS‐free patients. dnDSA prevalence in patients on IS maintenance was 44.4%. dnDSA development during IS minimization was a risk factor for acute rejection (P = 0.015). The majority of dnDSA were against HLA‐DQ antigens (78.7%). Conclusion. During the first year following transplantation, acute rejections increase the risk of developing dnDSA, so dnDSA positivity should be considered for IS withdrawal eligibility; during IS minimization, dnDSA development was associated with acute rejection, which prevented further IS withdrawal attempts.
The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical ...containment remain unclear. Here, we show that interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn's disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.
Noninvasive means for diagnosing acute rejection in kidney transplants are needed. This study prospectively measured mRNA in urinary cells from kidney-allograft recipients. A three-gene signature ...appeared to be diagnostic and prognostic of acute cellular rejection.
Kidney transplantation is considered the best available treatment for patients with end-stage renal disease (ESRD), but acute rejection, a leading cause of new cases of ESRD, undermines its full benefits.
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Acute rejection is diagnosed by means of needle biopsy. Over time, this invasive procedure has become safer, and biopsy interpretation more standardized.
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Nevertheless, bleeding and subsequent graft loss still occur, and sampling errors and interobserver variability in biopsy reading remain problematic.
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Repeated biopsies to assess the recipient's status pose challenges, including feasibility and cost.
Immunosuppressive drugs effectively treat acute rejection; a noninvasive means of diagnosing this reversible cause of . . .
The Model for End‐Stage Liver Disease (MELD) score predicts higher transplant healthcare utilization and costs; however, the independent contribution of functional status towards costs is ...understudied. The study objective was to evaluate the association between functional status, as measured by Karnofsky Performance Status (KPS), and liver transplant (LT) costs in the first posttransplant year. In a cohort of 598 LT recipients from July 1, 2009 to November 30, 2014, multivariable models assessed associations between KPS and outcomes. LT recipients needing full assistance (KPS 10%‐40%) vs being independent (KPS 80%‐100%) were more likely to be discharged to a rehabilitation facility after LT (22% vs 3%) and be rehospitalized within the first posttransplant year (78% vs 57%), all P < .001. In adjusted generalized linear models, in addition to MELD (P < .001), factors independently associated with higher 1‐year post‐LT transplant costs were older age, poor functional status (KPS 10%‐40%), living donor LT, pre‐LT hemodialysis, and the donor risk index (all P < .001). One‐year survival for patients in the top cost decile was 83% vs 93% for the rest of the cohort (log rank P < .001). Functional status is an important determinant of posttransplant resource utilization; therefore, standardized measurements of functional status should be considered to optimize candidate selection and outcomes.
This study examines the determinants of posttransplant healthcare utilization and costs among liver transplant recipients and identifies functional status at transplantation as an independent predictor of posttransplant costs, irrespective of MELD.
Viral persistence is associated with hierarchical antiviral CD8 T cell exhaustion with increased programmed death-1 (PD-1) expression. In HCV persistence, HCV-specific CD8 T cells from the liver (the ...site of viral replication) display increased PD-1 expression and a profound functional impairment that is not reversed by PD-1 blockade alone. Here, we report that the inhibitory receptor cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is preferentially upregulated in PD-1(+) T cells from the liver but not blood of chronically HCV-infected patients. PD-1/CTLA-4 co-expression in intrahepatic T cells was associated with a profound HCV-specific effector dysfunction that was synergistically reversed by combined PD-1/CTLA-4 blockade in vitro, but not by blocking PD-1 or CTLA-4 alone. A similar effect was observed in circulating HCV-specific CD8 T cells with increased PD-1/CTLA-4 co-expression during acute hepatitis C. The functional response to combined blockade was directly associated with CTLA-4 expression, lost with CD28-depletion and CD4-independent (including CD4(+)FoxP3(+) Tregs). We conclude that PD-1 and CTLA-4 pathways both contribute to virus-specific T cell exhaustion at the site of viral replication by a redundant mechanism that requires combined PD-1/CTLA-4 blockade to reverse. These findings provide new insights into the mechanisms of virus-specific T cell dysfunction, and suggest that the synergistic effect by combined inhibitory receptor blockade might have a therapeutic application against chronic viral infection in vivo, provided that it does not induce autoimmunity.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory ...elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 74 GWAS loci that have been associated with at least one complex phenotype. Our results reveal a repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.
...patients who are identified to be at risk for coronary heart disease, hypertension or diabetes using PRS at age of 25 would need a follow-up of 30 years to determine whether preemptive therapy ...impacts cumulative risk.1,2 THE ADVANTAGE OF STUDYING PRS IN THE TRANSPLANT SETTING The rapid development of metabolic syndrome complications in the transplant setting provides a more expedition and unique opportunity to test whether PRS can identify individuals at risk, set up preemptive protocols for the prevention of complications and determine whether changing the genetic environment via the introduction of the donor PRS can alter the clinical outcomes. Clinical studies using large databases demonstrated that within 12 months after transplantation, the incidence of new onset diabetes in all recipients is 15%–30%.3 Similar observations were reported for high prevalence soon after transplantation for hypertension, hyperlipidaemia and coronary heart disease.4–6 The ‘environmental variables’ that are responsible for a rapid development of these clinical complications are mainly the stress of surgery and the use of immunosuppressive drugs, many of which are known to be associated with the development of these chronic diseases (PMID: 32476781, PMID: 15093807). Knowing that immunosuppression drugs contribute significantly to these side effects, modifying immunosuppression protocols to use drug combinations and dosages that are tailored to each recipient may reduce the incidence of developing the complications. ...it will allow more intense monitoring of recipient at the higher risk for early intervention.
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