For more than a century, immunologists and vaccinologists have existed in parallel universes. Immunologists have for long reveled in using 'model antigens', such as chicken egg ovalbumin or nitrophenyl haptens, to study immune responses in model organisms such as mice. Such studies have yielded many seminal insights about the mechanisms of immune regulation, but their relevance to humans has been questioned. In another universe, vaccinologists have relied on human clinical trials to assess vaccine efficacy, but have done little to take advantage of such trials for studying the nature of immune responses to vaccination. The human model provides a nexus between these two universes, and recent studies have begun to use this model to study the molecular profile of innate and adaptive responses to vaccination. Such 'systems vaccinology' studies are beginning to provide mechanistic insights about innate and adaptive immunity in humans. Here, we present an overview of such studies, with particular examples from studies with the yellow fever and the seasonal influenza vaccines. Vaccination with the yellow fever vaccine causes a systemic acute viral infection and thus provides an attractive model to study innate and adaptive responses to a primary viral challenge. Vaccination with the live attenuated influenza vaccine causes a localized acute viral infection in mucosal tissues and induces a recall response, since most vaccinees have had prior exposure to influenza, and thus provides a unique opportunity to study innate and antigen-specific memory responses in mucosal tissues and in the blood. Vaccination with the inactivated influenza vaccine offers a model to study immune responses to an inactivated immunogen. Studies with these and other vaccines are beginning to reunite the estranged fields of immunology and vaccinology, yielding unexpected insights about mechanisms of viral immunity. Vaccines that have been proven to be of immense benefit in saving lives offer us a new fringe benefit: lessons in viral immunology.
The autoinducer-3 (AI-3)/epinephrine (Epi)/norepinephrine (NE) interkingdom signaling system mediates chemical communication between bacteria and their mammalian hosts. The three signals are sensed by the QseC histidine kinase (HK) sensor. Salmonella enterica serovar Typhimurium is a pathogen that uses HKs to sense its environment and regulate virulence. Salmonella serovar Typhimurium invades epithelial cells and survives within macrophages. Invasion of epithelial cells is mediated by the type III secretion system (T3SS) encoded in Salmonella pathogenicity island 1 (SPI-1), while macrophage survival and systemic disease are mediated by the T3SS encoded in SPI-2. Here we show that QseC plays an important role in Salmonella serovar Typhimurium pathogenicity. A qseC mutant was impaired in flagellar motility, in invasion of epithelial cells, and in survival within macrophages and was attenuated for systemic infection in 129x1/SvJ mice. QseC acts globally, regulating expression of genes within SPI-1 and SPI-2 in vitro and in vivo (during infection of mice). Additionally, dopamine β-hydroxylase knockout (Dbh -/- ) mice that do not produce Epi or NE showed different susceptibility to Salmonella serovar Typhimurium infection than wild-type mice. These data suggest that the AI-3/Epi/NE signaling system is a key factor during Salmonella serovar Typhimurium pathogenesis in vitro and in vivo. Elucidation of the role of this interkingdom signaling system in Salmonella serovar Typhimurium should contribute to a better understanding of the complex interplay between the pathogen and the host during infection.
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Luciano J. Costa;
Mei-Jie Zhang;
Xiaobo Zhong;
Angela Dispenzieri;
Sagar Lonial;
Amrita Krishnan;
Cesar Freytes;
David Vesole;
Robert Peter Gale;
Kenneth Anderson;
Baldeep Wirk;
Edmund Waller;
Bipin Savani;
Harry Schouten;
Hillard Lazarus;
Kenneth Meehan;
Manish Sharma;
Rammurti Kamble;
Ravi Vij;
Shaji Kumar
The impact of novel drugs for treating multiple myeloma (MM) on the utilization and outcomes of autologous hematopoietic progenitor cell transplantation (AHPCT) is unknown. We reviewed characteristics and outcomes of 20,278 patients who underwent AHPCT within 12months of diagnosis of MM in the United States and Canada and registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) in 3 time cohorts reflecting the increasing availability of novel drugs: 1995 to 1999 (n=2226), 2000 to 2004 (n=6408), and 2005 to 2010 (n=11,644). In the United States, the number of AHPCTs performed increased at a greater rate than new MM cases. Patients in recent cohorts were older, less likely to have stage 3MM, and more likely to have received previous thalidomide, lenalidomide, or bortezomib. On multivariate analysis, AHPCT in the 2000 to 2004 cohort (HR=0.77) or in the 2005 to 2010 cohort (HR=0.68) were associated with lower risk of death. Survival at 60months post-AHPCT improved from 47% in 1995 to 1999 to 55% in 2000 to 2004 and to 57% in 2005 to 2010, owing less to improvement in progression-free survival (50% versus 55% versus 57% at 24months) than to postrelapse/progression survival (58% versus 65% versus 72% at 24months). AHPCT and new biological agents are complementary, nonredundant therapies and should be combined in the management of MM in suitable patients.
In addition to their well characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of immune responses. However, their contribution to autoimmune and neurologic disease processes has not been investigated. Experimental allergic encephalomyelitis (EAE) and its human disease counterpart, multiple sclerosis, are considered to be CD4+ T cell-mediated autoimmune diseases affecting the central nervous system. Several lines of indirect evidence suggest that mast cells could also play a role in the pathogenesis of both the human and murine disease. Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell-deficient W/W(v) mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates. No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/W(v) animals. Reconstitution of the mast cell population in W/W(v) mice restores induction of early and severe disease to wild-type levels, suggesting that mast cells are critical for the full manifestation of disease. These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.
Tumor-specific mutations can result in immunogenic neoantigens, both of which have been correlated with responsiveness to immune checkpoint inhibitors in highly mutagenic cancers. However, early results of single-agent checkpoint inhibitors in multiple myeloma (MM) have been underwhelming. Therefore, we sought to understand the relationship between mutation and neoantigen landscape of MM patients and responsiveness to therapies. Somatic mutation burden, neoantigen load, and response to therapy were determined using interim data from the MMRF CoMMpass study (NCT01454297) on 664 MM patients. In this population, the mean somatic and missense mutation loads were 405.84(s=608.55) and 63.90(s=95.88) mutations per patient, respectively. There was a positive linear relationship between mutation and neoantigen burdens (R2=0.862). The average predicted neoantigen load was 23.52(s=52.14) neoantigens with an average of 9.40(s=26.97) expressed neoantigens. Survival analysis revealed significantly shorter progression-free survival (PFS) in patients with greater than average somatic missense mutation load (N=163, 0.493 vs 0.726 2-year PFS, P=0.0023) and predicted expressed neoantigen load (N=214, 0.555 vs 0.729 2-year PFS, P=0.0028). This pattern is maintained when stratified by disease stage and cytogenetic abnormalities. Therefore, high mutation and neoantigen load are clinically relevant risk factors that negatively impact survival of MM patients under current standards of care.
Purpose of review: A key factor driving AIDS-associated immunopathogenesis is chronic immune activation. Simian immunodeficiency virus (SIV) infection of African natural host species leads to high viremia, but low immune activation and absence of disease. Considerable progress in our understanding of pathological immune activation has come from comparative studies of SIV infection in pathogenic Asian macaque species and natural hosts. The focus of this review is to highlight recent work on the natural host model using high-throughput genomics.
Recent findings: Several groups have independently conducted microarray gene expression profiling comparing in-vivo SIV infection in natural and non-natural hosts. A consistent finding between these studies is that both pathogenic SIV infection of macaques and nonpathogenic infections of natural hosts have strong induction of interferon-stimulated genes (ISGs) early on, but a key difference was that natural hosts down-modulated the interferon response rapidly after acute infection. The development of new genome-based resources for further study of the natural host model is discussed.
Summary: Initial efforts using high-throughput biology to study SIV infection of natural hosts have effectively identified the ability of natural hosts to resolve interferon responses and immune activation. Further application of 'omic-based technologies coupled with integrative systems-based analysis should continue to yield progress.
Antimicrobial resistance is increasing in nearly all health-care-associated pathogens. We examined changes in resistance prevalence during 1996-1999 in 23 hospitals by using two statistical methods. When the traditional chi-square test of pooled mean resistance prevalence was used, most organisms appear to have increased in prevalence. However, when a more conservative test that accounts for changes within individual hospitals was used, significant increases in prevalence of resistance were consistently observed only for oxacillin-resistant Staphylococcus aureus, ciprofloxacin-resistant Pseudomonas aeruginosa, and ciprofloxacin- or ofloxacin-resistant Escherichia coli. These increases were significant only in isolates from patients outside intensive-care units (ICU). The increases seen are of concern; differences in factors present outside ICUs, such as excessive quinolone use or inadequate infection-control practices, may explain the observed trends.
We describe the Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance system. Elements of the system critical for successful reduction of nosocomial infection rates include voluntary participation and confidentiality; standard definitions and protocols; identification of populations at high risk; site-specific, risk-adjusted infection rates comparable across institutions; adequate numbers of trained infection control professionals; dissemination of data to health-care providers; and a link between monitored rates and prevention efforts.
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Richard Platt;
Ken Kleinman;
Kristin Thompson;
Rachel S. Dokholyan;
James M. Livingston;
Andrew Bergman;
John H. Mason;
Teresa C. Horan;
Robert Gaynes;
Steven L. Solomon;
Kenneth E. Sands
We determined if infection indicators were sufficiently consistent across health plans to allow comparison of hospitals' risks of infection after coronary artery bypass surgery. Three managed care organizations accounted for 90% of managed care in eastern Massachusetts, from October 1996 through March 1999. We searched their automated inpatient and outpatient claims and outpatient pharmacy dispensing files for indicator codes suggestive of postoperative surgical site infection. We reviewed full text medical records of patients with indicator codes to confirm infection status. We compared the hospital-specific proportions of cases with an indicator code, adjusting for health plan, age, sex, and chronic disease score. A total of 536 (27%) of 1,953 patients had infection indicators. Infection was confirmed in 79 (53%) of 149 reviewed records with adequate documentation. The proportion of patients with an indicator of infection varied significantly (p < 0.001) between hospitals (19% to 36%) and health plans (22% to 33%). The difference between hospitals persisted after adjustment for health plan and patients' age and sex. Similar relationships were observed when postoperative antibiotic information was ignored. Automated claims and pharmacy data from different health plans can be used together to allow inexpensive, routine monitoring of indicators of postoperative infection, with the goal of identifying institutions that can be further evaluated to determine if risks for infection can be reduced.
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Benjamin Besse;
Melinda Charrier;
Valerie Lapierre;
Eric Dansin;
Olivier Lantz;
David Planchard;
Thierry Le Chevalier;
Alain Livartoski;
Fabrice Barlesik;
Agnes Laplanche;
Stephanie Ploix;
Nadege Vimond;
Isabelle Peguillet;
Clotilde Thery;
Ludovic Lacroix;
Inka Zoernig;
Kavita Dhodapkar;
Madhav Dhodapkar;
Sophie Viaud;
Jean-Charles Soria;
Katrin S. Reiners;
Elke Pogge von Strandmann;
Frederic Vely;
Sylvia Rusakiewicz;
Alexander Eggermont;
Jonathan M. Pitt;
Laurence Zitvogel;
Nathalie Chaput
ABSTRACT: Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.