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IntroductionA major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.MethodsBlood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry.ResultsLymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).ConclusionsIn vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

Our aim was to obtain knowledge of how meteorological conditions affect community epidemics of respiratory syncytial virus (RSV) infection. To this end we recorded year-round RSV activity in nine cities that differ markedly in geographic location and climate. We correlated local weather conditions with weekly or monthly RSV cases. We reviewed similar reports from other areas varying in climate. Weekly RSV activity was related to temperature in a bimodal fashion, with peaks of activity at temperatures above 24-30 degrees C and at 2-6 degrees C. RSV activity was also greatest at 45-65% relative humidity. RSV activity was inversely related to UVB radiance at three sites where this could be tested. At sites with persistently warm temperatures and high humidity, RSV activity was continuous throughout the year, peaking in summer and early autumn. In temperate climates, RSV activity was maximal during winter, correlating with lower temperatures. In areas where temperatures remained colder throughout the year, RSV activity again became nearly continuous. Community activity of RSV is substantial when both ambient temperatures and absolute humidity are very high, perhaps reflecting greater stability of RSV in aerosols. Transmission of RSV in cooler climates is inversely related to temperature possibly as a result of increased stability of the virus in secretions in the colder environment. UVB radiation may inactivate virus in the environment, or influence susceptibility to RSV by altering host resistance.

IntroductionConvincing evidence exists for a protective role of cellular immunity in HIV infection. For example, virologic control and detection of HIV-specific cytotoxic T lymphocytes (CTLs) are temporally related during primary HIV infection, 1 and CD8 T-cell depletion results in widespread virus replication and disease progression in the simian immunodeficiency virus (SIV)-infected nonhuman primate model. In HIV infection, the failure of antiviral immunity has been attributed in part to qualitative CTL defects 2-4 such as decreased perforin in total-and HIV-specific CD8 T cells in peripheral blood and lymphoid tissue, including gutassociated lymphoid tissues. [5][6][7][8] Perforin defects are also evident in CTLs of patients who are on highly active antiretroviral therapy (HAART). 2,9 The inability of most patients to keep HIV under control in the absence of potent antiretroviral therapy 10,11 has led to the quest for immunotherapeutic approaches to augment antiviral cellular immunity.CD8 T cells can be identified phenotypically for their maturation status based upon expression of cell-surface maturation markers. For example, naive, central memory, effector memory, and effector subsets manifest differential expression of CD45RA and CD62L or CCR7, 12 and perturbations in their distribution have been identified in HIV infection. Typically, naive and effector CD8 T cells are reduced, and effector memory subsets are expanded in patients with HIV who have only partial restoration with HAART. [1][2][3] The major mechanism by which effector CD8 T cells kill virusinfected targets and tumor cells is via secretion of lytic molecules, namely perforin and granzymes. 13,14 Lytic granules in CTLs are stored in a dense core within secretory lysosomes, 15 and the membrane that encloses the granules contains lysosomal glycoproteins such as lysosome-associated membrane protein-1 (LAMP-1; CD107a), LAMP-2 (CD107b), and CD63. 16 Soluble granule contents are released during exocytosis, and the incorporation of granule membrane proteins such as CD107a into the plasma membrane serve as markers of degranulation.Preservation of memory and effector CD8 T-cell pools in vivo depends in part upon homeostatic proliferation which is regulated by cytokines and self-peptide MHC ligands for the T-cell receptor (TCR). It is now widely accepted that generation of long-term memory CD4 and CD8 T cells is dependent upon antigenic stimulation, but their survival is antigen independent and requires peripherally produced cytokines, particularly those that use the common ␥-chain for signaling, such as interleukin (IL)-15. [17][18][19] Another more recently described pleiotropic cytokine that uses the common ␥-chain is IL-21, which is produced only by activated CD4 T lymphocytes and has significant sequence similarity to cytokines IL-2, Based on the known T-cell-potentiating properties of IL-21 in tumor models, 26,27 we hypothesized that IL-21 could augment the effector function of CD8 T cells in patients with HIV. Patients, materials, and methods Stu...

Our data suggest that the presence of a prominent Ito in epicardium contributes the development of marked electrical heterogeneity in the ventricle after exposure to flecainide. Flecainide-induced dispersion of repolarization, especially when accompanied by prominent conduction delays, results in extrasystolic activity via a mechanism that we have termed "phase 2 reentry." Our results also suggest a role for Ito blockers in the treatment of reentrant arrhythmias.