The role of the NKG2D receptor for tumor immunity.

Natural killer (NK) cells have originally been identified based on their capacity to kill transformed cells in a seemingly non-specific fashion. Over the last 15 years, knowledge on receptor ligand systems used by NK cells to specifically detect transformed cells has been accumulating rapidly. One of these receptor ligand systems, the NKG2D pathway, has received particular attention, and now serves as a paradigm for how the immune system is able to gather information about the health status of autologous host cells. In addition to its significance on NK cells, NKG2D, as well as other NK cell receptors, play significant roles on T cells. This review aims at summarizing recent insights into the regulation of NKG2D function, the control over NKG2D ligand expression and the role of NKG2D in tumor immunity. Finally, we will discuss first attempts to exploit NKG2D function to improve immunity to tumors.

Regulation of protective immunity against Leishmania major in mice.

Resolution of lesions induced by Leishmania major in mice results from the development of Th1 responses. Cytokines produced by Th1 cells activate macrophages to a parasiticidal state. The development of Th2 responses in mice from a few strains underlies susceptibility to infection. Cytokines produced by Th2 cells exacerbate the development of lesions because of their deactivating properties for macrophages. This murine model of infection has provided significant insight into the mechanisms intrinsic to the differentiation of disparate CD4+ T cell subsets in vivo in animals from different genetic backgrounds.

A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients.

BACKGROUND: Community-acquired respiratory viral infections (RVIs) are common in lung transplant patients and may be associated with acute rejection and bronchiolitis obliterans syndrome (BOS). The use of sensitive molecular methods that can simultaneously detect a large panel of respiratory viruses may help better define their effects. METHODS: Lung transplant recipients undergoing serial surveillance and diagnostic bronchoalveolar lavages (BALs) during a period of 3 years were enrolled. BAL samples underwent multiplex testing for a panel of 19 respiratory viral types/subtypes using the Luminex xTAG respiratory virus panel assay. RESULTS: Demographics, symptoms, and forced expiratory volume in 1 sec were prospectively collected for 93 lung transplant recipients enrolled. Mean number of BAL samples was 6.2+/-3.1 per patient. A respiratory virus was isolated in 48 of 93 (51.6%) patients on at least one BAL sample. Of 81 positive samples, the viruses isolated included rhinovirus (n=46), parainfluenza 1 to 4 (n=17), coronavirus (n=11), influenza (n=4), metapneumovirus (n=4), and respiratory syncytial virus (n=2). Biopsy-proven acute rejection (> or =grade 2) or decline in forced expiratory volume in 1 sec > or =20% occurred in 16 of 48 (33.3%) patients within 3 months of RVI when compared with 3 of 45 (6.7%) RVI-negative patients within a comparable time frame (P=0.001). No significant difference was seen in incidence of acute rejection between symptomatic and asymptomatic patients. Biopsy-proven obliterative bronchiolitis or BOS was diagnosed in 10 of 16 (62.5%) patients within 1 year of infection. CONCLUSION: Community-acquired RVIs are frequently detected in BAL samples from lung transplant patients. In a significant percentage of patients, symptomatic or asymptomatic viral infection is a trigger for acute rejection and obliterative bronchiolitis/BOS.

Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity.

In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8(+) T cells. In spite of the large number of tumor-specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumor-infiltrating lymphocytes revealed that specific anti-tumor CD8(+) T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity.

Prise en charge de la pneumonie communautaire [Management of community acquired pneumonia]

Une grande partie des patients présentant une pneumonie communautaire ont un bon pronostic et peuvent être suivis dans la pratique ambulatoire moyennant un nombre limité d'examens paracliniques. Le diagnostic repose sur une clinique suggestive en présence d'un infiltrat compatible avec une pneumonie à la radiographie de thorax. Une anamnèse de voyage et une bonne connaissance de résistances locales du pneumocoque aux antibiotiques sont déterminantes pour le choix du traitement. Pour les patients de moins de 50 ans sans comorbidités et sans signes de sévérité, il est généralement recommandé de prescrire un macrolide ou une fluoroquinolone de 3e ou de 4e génération (fluoroquinolones «respiratoires»). Pour les patients plus âgés, et pour ceux qui présentent des comorbidités ou des critères de sévérité, une évaluation à l'hôpital est indiquée. La majorité des patients hospitalisés en soins généraux peuvent être traités par l'association d'une bêta-lactame et d'un macrolide, ou par une fluoroquinolone «respiratoire» seule, après prélèvements d'expectorations et de sang pour culture.

The human T cell response to melanoma antigens.

The cornerstone of the concept of immunosurveillance in cancer should be the experimental demonstration of immune responses able to alter the course of in vivo spontaneous tumor progression. Elegant genetic manipulation of the mouse immune system has proved this tenet. In parallel, progress in understanding human T cell mediated immunity has allowed to document the existence in cancer patients of naturally acquired T cell responses to molecularly defined tumor antigens. Various attributes of cutaneous melanoma tumors, notably their adaptability to in vitro tissue culture conditions, have contributed to convert this tumor in the prototype for studies of human antitumor immune responses. As a consequence, the first human cytolytic T lymphocyte (CTL)-defined tumor antigen and numerous others have been identified using lymphocyte material from patients bearing this tumor, detailed analyses of specific T cell responses have been reported and a relatively large number of clinical trials of vaccination have been performed in the last 15 years. Thus, the "melanoma model" continues to provide valuable insights to guide the development of clinically effective cancer therapies based on the recruitment of the immune system. This chapter reviews recent knowledge on human CD8 and CD4 T cell responses to melanoma antigens.

Comparison of hospital-wide and unit-specific cumulative antibiograms in hospital- and community-acquired infection.

BACKGROUND: Empirical antibacterial therapy in hospitals is usually guided by local epidemiologic features reflected by institutional cumulative antibiograms. We investigated additional information inferred by aggregating cumulative antibiograms by type of unit or according to the place of acquisition (i.e. community vs. hospital) of the bacteria. MATERIALS AND METHODS: Antimicrobial susceptibility rates of selected pathogens were collected over a 4-year period in an university-affiliated hospital. Hospital-wide antibiograms were compared with those selected by type of unit and sampling time (<48 or >48 h after hospital admission). RESULTS: Strains isolated >48 h after admission were less susceptible than those presumably arising from the community (<48 h). The comparison of units revealed significant differences among strains isolated >48 h after admission. When compared to hospital-wide antibiograms, susceptibility rates were lower in the ICU and surgical units for Escherichia coli to amoxicillin-clavulanate, enterococci to penicillin, and Pseudomonas aeruginosa to anti-pseudomonal beta-lactams, and in medical units for Staphylococcus aureus to oxacillin. In contrast, few differences were observed among strains isolated within 48 h of admission. CONCLUSIONS: Hospital-wide antibiograms reflect the susceptibility pattern for a specific unit with respect to community-acquired, but not to hospital-acquired strains. Antibiograms adjusted to these parameters may be useful in guiding the choice of empirical antibacterial therapy.

Nasal immunization of mice with virus-like particles protects offspring against rotavirus diarrhea.

Rotavirus is the major cause of diarrhea among young infants in both humans and animals. Immune protection of newborns by vaccination is difficult to achieve since there is not enough time to mount an immune response before exposure to the virus. We have designed a vaccination strategy mediating transfer of neutralizing antibodies from the mother to the offspring during pregnancy and/or lactation. Adult female mice were nasally immunized with virus-like particles (VLPs) made of viral proteins VP2 and 6 (VLP2/6) or VP 2, 6, and 7 (VLP2/6/7) derived from the RF rotavirus strain in the presence or absence of cholera toxin. Both vaccines elicited serum and milk antibodies against the respective VPs. Four days after parturition, suckling pups were challenged orally with RF rotavirus. Pups from mothers immunized with VLP2/6/7 but not VLP2/6 were protected against rotavirus diarrhea, indicating that VP7 plays a key role in protection. Protection was mediated by milk rather than serum antibodies, and mucosal adjuvants were not required. In conclusion, VLPs containing VP7 administered nasally to mothers represent a promising vaccine candidate for the protection of suckling newborns against rotavirus-induced diarrhea, even in the absence of a mucosal adjuvant.

Genital Chlamydia trachomatis: understanding the roles of innate and adaptive immunity in vaccine research.

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide, and despite significant advances in chlamydial research, a prophylactic vaccine has yet to be developed. This Gram-negative obligate intracellular bacterium, which often causes asymptomatic infection, may cause pelvic inflammatory disease (PID), ectopic pregnancies, scarring of the fallopian tubes, miscarriage, and infertility when left untreated. In the genital tract, Chlamydia trachomatis infects primarily epithelial cells and requires Th1 immunity for optimal clearance. This review first focuses on the immune cells important in a chlamydial infection. Second, we summarize the research and challenges associated with developing a chlamydial vaccine that elicits a protective Th1-mediated immune response without inducing adverse immunopathologies.

Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors.

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.

Determinants of vaccine immunity in the cohort of human immunodeficiency virus-infected children living in Switzerland.

BACKGROUND: Human immunodeficiency virus (HIV)-infected children are at increased risk of infections caused by vaccine preventable pathogens, and specific immunization recommendations have been issued. METHODS: A prospective national multicenter study assessed how these recommendations are followed in Switzerland and how immunization history correlates with vaccine immunity. RESULTS: Among 87 HIV-infected children (mean age: 11.1 years) followed in the 5 Swiss university hospitals and 1 regional hospital, most (76%) had CD4 T cells >25%, were receiving highly active antiretroviral treatment (79%) and had undetectable viral load (60%). Immunization coverage was lower than in the general population and many lacked serum antibodies to vaccine-preventable pathogens, including measles (54%), varicella (39%), and hepatitis B (65%). The presence of vaccine antibodies correlated most significantly with having an up-to-date immunization history (P<0.05). An up-to-date immunization history was not related to age, immunologic stage, or viremia but to the referral medical center. CONCLUSIONS: All pediatricians in charge of HIV-infected children are urged to identify missing immunizations in this high-risk population.

Severe Postnatally Acquired Cytomegalovirus Infection Presenting with Colitis, Pneumonitis and Sepsis-Like Syndrome in an Extremely Low Birthweight Infant

Few cases of severe postnatally acquired cytomegalovirus (CMV) infection are reported in premature infants. We report on an extremely low birthweight (ELBW) preterm infant who presented with a sepsis-like syndrome and multiple organ involvement, notably pneumonitis and colitis. The course of infection was assessed by repeated analysis of urine, tracheal aspirates and blood. The patient was given intravenous ganciclovir. The clinical course was rapidly favorable. Development of neutropenia led to the discontinuation of the antiviral treatment after 28 days. Follow-up showed moderate white matter anomalies on cerebral MRI, a transient hypoacusis and a mild developmental delay at 18 months of corrected age. To the best of our knowledge, this is the first description of a severe combination of pneumonitis and colitis in postnatal CMV infection. Many issues remain controversial and are discussed. We propose that antiviral treatment should be considered in severe postnatal CMV infection in ELBW patients.

Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients.

Late-onset cytomegalovirus (CMV) disease commonly occurs after discontinuation of antiviral prophylaxis. We determined the utility of testing CD8+ T-cell response against CMV as a predictor of late-onset CMV disease after a standard course of antiviral prophylaxis. Transplant patients at high-risk for CMV disease were enrolled. CD8+ T-cell-mediated immunity (CMI) was tested using the QuantiFERON-CMV assay at baseline, 1, 2 and 3 months posttransplant by measurement of interferon-gamma response to whole blood stimulation with a 21-peptide pool. The primary outcome was the ability of CMI testing to predict CMV disease in the first 6 months posttransplant. There were 108 evaluable patients (D+/R+ n = 39; D-/R+ n = 34; D+/R- n = 35) of whom 18 (16.7%) developed symptomatic CMV disease. At the end of prophylaxis, CMI was detectable in 38/108 (35.2%) patients (cutoff 0.1 IU/mL interferon-gamma). CMV disease occurred in 2/38 (5.3%) patients with a detectable interferon-gamma response versus 16/70 (22.9%) patients with a negative response; p = 0.038. In the subgroup of D+/R- patients, CMV disease occurred in 1/10 (10.0%) patients with a detectable interferon-gamma response (cutoff 0.1 IU/mL) versus 10/25 (40.0%) patients with a negative CMI, p = 0.12. Monitoring of CMI may be useful for predicting late-onset CMV disease.