Background
Outcomes from Gram‐negative bacteremia (GNB) in solid organ transplant (SOT) recipients are poorly understood.
Methods
This is a single center prospective cohort study comparing the ...clinical characteristics and outcomes of SOT recipients with GNB to immunocompetent non‐SOT patients with GNB between 1/1/2002 through 12/31/2018. Outcomes of interest included incidence of septic shock, respiratory failure, and time to death. A multivariable logistic regression model was used to determine factors associated with incidence of septic shock and respiratory failure. Time to death was evaluated using Cox proportional hazard models.
Results
A total of 297 SOT and 1245 immunocompetent non‐SOT patients were included. Incidence of septic shock did not significantly differ between the groups (SOT 25.3% vs. non‐SOT 24.6%, p = .8225). Overall survival did not significantly differ by transplant status (30‐day survival: SOT 76%, 95% confidence interval CI 70, 92, non‐SOT 74%, 95% CI 71, 77: log rank: p = .76). SOT recipients taking three immunosuppressive medications had significantly lower odds of developing septic shock or respiratory failure requiring intubation and mechanical ventilation than those taking ≤1 agent (shock: adjusted odds ratio aOR 0.29, 95% CI 0.09, 0.90, p = .0316; respiratory failure: aOR 0.14, 95% CI: 0.04, 0.49, p = .0020).
Conclusions
SOT recipients with GNB do not experience higher rates of septic shock, respiratory failure, or mortality than immnon‐SOT recipients with GNB. Among SOT recipients, a greater number of immunosuppressive medications may be associated with improved outcomes during GNB. Future studies are needed to understand the potential relationship between levels of immunosuppression and clinical outcome in SOT recipients with GNB.
Chronic activation of the immune system in HIV infection is one of the strongest predictors of morbidity and mortality. As such, approaches that reduce immune activation have received considerable ...interest. Previously, we demonstrated that administration of a type I interferon receptor antagonist (IFN-1ant) during acute SIV infection of rhesus macaques results in increased virus replication and accelerated disease progression. Here, we administered a long half-life PASylated IFN-1ant to ART-treated and ART-naïve macaques during chronic SIV infection and measured expression of interferon stimulated genes (ISG) by RNA sequencing, plasma viremia, plasma cytokines, T cell activation and exhaustion as well as cell-associated virus in CD4 T cell subsets sorted from peripheral blood and lymph nodes. Our study shows that IFN-1ant administration in both ART-suppressed and ART-untreated chronically SIV-infected animals successfully results in reduction of IFN-I-mediated inflammation as defined by reduced expression of ISGs but had no effect on plasma levels of IL-1β, IL-1ra, IL-6 and IL-8. Unlike in acute SIV infection, we observed no significant increase in plasma viremia up to 25 weeks after IFN-1ant administration or up to 15 weeks after ART interruption. Likewise, cell-associated virus measured by SIV gag DNA copies was similar between IFN-1ant and placebo groups. In addition, evaluation of T cell activation and exhaustion by surface expression of CD38, HLA-DR, Ki67, LAG-3, PD-1 and TIGIT, as well as transcriptome analysis showed no effect of IFN-I blockade. Thus, our data show that blocking IFN-I signaling during chronic SIV infection suppresses IFN-I-related inflammatory pathways without increasing virus replication, and thus may constitute a safe therapeutic intervention in chronic HIV infection.
Donor‐specific antibodies (DSAs) contribute to renal allograft loss. However, biomarkers to guide clinical management of DSA posttransplant or detect humoral alloimmune responses before ...alloantibodies develop are not available. Circulating T follicular helper (cTfh) cells are CD4+CXCR5+ Tfh‐like cells in the blood that have been associated with alloantibodies in transplant recipients, but whether they precede antibody formation for their evaluation as a predictive biomarker in transplant is unknown. To evaluate the ability of cTfh cells to predict DSA, we used murine transplant models to determine the temporal relationship between cTfh cells, germinal center formation, and DSA development. We observed that donor‐reactive CD4+CXCR5+ cTfh cells expand after allotransplant. These cTfh cells were equivalent to graft‐draining lymph node‐derived Tfh cells in their ability to provide B cell help for antibody production. cTfh cell expansion and differentiation into ICOS+PD‐1+ cells temporally correlated with germinal center alloreactivity and preceded the generation of DSAs in instances of modified and unmodified alloantibody formation. Importantly, delayed costimulation blockade initiated after the detection of ICOS+PD‐1+ cTfh cells prevented DSAs. These findings suggest that cTfh cells could serve as a biomarker for humoral alloreactivity before the detection of alloantibodies and inform therapeutic approaches to prevent DSAs.
This study evaluates the relationship between circulating T follicular helper cells and alloantibody formation in a mouse transplant model, identifying that detectable changes in these T follicular helper‐like cells in the blood precede the development of donor‐specific antibody in the event of modified and unmodified antibody formation and therefore could potentially serve as a biomarker for humoral alloreactivity.
A recent study reveals the presence of lymphatic vessels that transport both immune cells and lymph within the central nervous system, and has relevance for infectious and malignant complications ...occurring in immunosuppressed individuals.
Intestinal epithelial expression of the tight junction protein claudin-2, which forms paracellular cation and water channels, is precisely regulated during development and in disease. Here, we show ...that small intestinal epithelial claudin-2 expression is selectively upregulated in septic patients. Similar changes occurred in septic mice, where claudin-2 upregulation coincided with increased flux across the paracellular pore pathway. In order to define the significance of these changes, sepsis was induced in claudin-2 knockout (KO) and wild-type (WT) mice. Sepsis-induced increases in pore pathway permeability were prevented by claudin-2 KO. Moreover, claudin-2 deletion reduced interleukin-17 production and T cell activation and limited intestinal damage. These effects were associated with reduced numbers of neutrophils, macrophages, dendritic cells, and bacteria within the peritoneal fluid of septic claudin-2 KO mice. Most strikingly, claudin-2 deletion dramatically enhanced survival in sepsis. Finally, the microbial changes induced by sepsis were less pathogenic in claudin-2 KO mice as survival of healthy WT mice injected with cecal slurry collected from WT mice 24 h after sepsis was far worse than that of healthy WT mice injected with cecal slurry collected from claudin-2 KO mice 24 h after sepsis. Claudin-2 upregulation and increased pore pathway permeability are, therefore, key intermediates that contribute to development of dysbiosis, intestinal damage, inflammation, ineffective pathogen control, and increased mortality in sepsis. The striking impact of claudin-2 deletion on progression of the lethal cascade activated during sepsis suggests that claudin-2 may be an attractive therapeutic target in septic patients.
Abstract The regulatory circuits dictating CD8 + T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating ...antigen-specific PD-1 + TCF-1 − CD8 + T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8 + T cells prolongs CD8 + T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1 + CD8 + T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8 + T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2 -expressing CD8 + T cells, when compared to Fgl2 -deficient CD8 + T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8 + T cell-expressed FcγRIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1 + CD8 + T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity.
Since the discovery of the CD40-CD154 costimulatory pathway and its critical role in the adaptive immune response, there has been considerable interest in therapeutically targeting this interaction ...with monoclonal antibodies in transplantation. Unfortunately, initial promise in animal models gave way to disappointment in clinical trials following a number of thromboembolic complications. However, recent mechanistic studies have identified the mechanism of these adverse events, as well as detailed a myriad of interactions between CD40 and CD154 on a wide variety of immune cell types and the critical role of this pathway in generating both humoral and cell-mediated alloreactive responses. This has led to resurgence in interest and the potential resurrection of anti-CD154 and anti-CD40 antibodies as clinically viable therapeutic options.
Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical ...therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration–approved drugs.
Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule ...expressed predominantly on NK cells and memory CD8
T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4
T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4
T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4
T cells in mediating immune dysregulation.
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