Interactions of Human Myeloid Cells with Natural Killer Cell Subsets In Vitro and In Vivo

In both human and mouse it has been recently realized that natural killer (NK) cells do not emerge from the bone marrow with full functional competence but rather acquire functions in interaction with antigen-presenting cells (APCs), primarily dendritic cells (DCs). Here we review the mechanisms and the consequences of this NK-cell preactivation, as well as discuss new experimental models that now allow investigating these interactions for human NK cells and their response to human pathogens in vivo. These investigations will allow harnessing NK cells during vaccination for improved innate and adaptive immunity

Natural killer cells in herpesvirus infections

Natural killer (NK) cells are potent innate cytotoxic lymphocytes for the destruction of infected and transformed cells. Although they were originally considered to be ready-made assassins after their hematopoietic development, it has recently become clear that their activity is regulated by mechanisms such as repertoire composition, licensing, priming, and adaptive memory-like differentiation. Some of these mechanisms are influenced by infectious disease agents, including herpesviruses. In this review, we will compare expansion, stimulation, and effector functions of NK cell populations after infections with β- and γ 1-herpesviruses because, though closely related, these pathogens seem to drive completely opposite NK cell responses. The discussed findings suggest that different NK cell subsets expand and perform protective functions during infectious diseases and might be used diagnostically to predict resistance to the causative pathogens as well as treat them by adoptive transfer of the respective populations

Hepatitis E Virus Detection in Liver Tissue from Patients with Suspected Drug-Induced Liver Injury

Hepatitis E virus (HEV) infection is increasingly recognized as a cause of acute hepatitis in the industrialized world. We aimed to determine the frequency of acute Hepatitis E virus (HEV) infection in cases of suspected drug-induced liver injury (DILI), mainly a diagnosis of exclusion. To this aim, formalin-fixed, paraffin-embedded (FFPE) liver tissues of all cases routinely processed in our institute during a 2 ½ years period in which DILI was amongst the differential diagnoses (157 liver biopsies, one liver explant) were subjected to semi-nested RT-PCR for the detection of hepatitis E virus (HEV) RNA. Histopathology was re-evaluated on all cases tested positive. HEV RNA was detectable in three of 158 cases (2%) tested, comprising autochthonic as well as travel-related infections with genotypes 1, 3, and 4 each found once, respectively. Histopathologic findings comprised one case with subtotal hepatic necrosis and two cases of acute (cholestatic) hepatitis not distinguishable from acute hepatitis of other etiology. Thus, the overall frequency of acute hepatitis E virus (HEV) infection as determined by detection of hepatitis E virus (HEV) RNA in liver tissue is substantially increased in patients with suspected drug-induced liver injury compared to the healthy population, emphasizing the need to actively look for hepatitis E virus (HEV) infection in cases of suspected drug-induced liver injury (DILI). Molecular testing for hepatitis E virus (HEV) RNA in routinely processed formalin-fixed, paraffin-embedded (FFPE) liver tissues can be applied to cases with undetermined hepatitis E virus (HEV) status

Role of the 2B4 Receptor in CD8+ T-Cell-Dependent Immune Control of Epstein-Barr Virus Infection in Mice With Reconstituted Human Immune System Components

Patients with X-linked lymphoproliferative (XLP) disease due to deficiency in the adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) are highly susceptible to one specific viral pathogen, the Epstein-Barr virus (EBV). This susceptibility might result from impaired CD8+ T-cell and natural killer cell responses to EBV infection in these patients. We demonstrate that antibody blocking of the SAP-dependent 2B4 receptor is sufficient to induce XLP-like aggravation of EBV disease in mice with reconstituted human immune system components. CD8+ T cells require 2B4 for EBV-specific immune control, because 2B4 blockade after CD8+ T-cell depletion did not further aggravate symptoms of EBV infectio

The Challenges of Establishing Universal Health Coverage in Enugu State, South East Nigeria

This research was supported by UNN TETFUND Committee through TETFUND Institution Based Research Fund. Abstract Background: Financial risk protection for healthcare is deficient in Enugu state, Southeast Nigeria and the worst affected are the rural dwellers and the poorest, thus creating both socioeconomic and geographic inequity in access and use of services. The study aimed at eliciting the level of awareness and use of pre-payment mechanisms, and more importantly, determining the economic and political factors that facilitate or constrain achievement of Universal Health Coverage in Enugu state, Southeast Nigeria. Methods: Study was conducted in two purposively chosen urban and rural local government areas(LGA) of Enugu state with mixed method study design. Cross-sectional household questionnaire survey was conducted on 802 sample size from the two LGAs and 12 key informants participated in In-depth interviews (IDIs). The quantitative data was analysed with STATA using descriptive statistics while the qualitative IDI data was organized into nodes and sub-nodes using Nvivo: political and economic factors, corruption, communication/Awareness, capacity development / Infrastructure, policy development, leadership and referral system. Later, findings were thematically analysed. Results: The survey results showed that 84% of the study sample have secondary school education and 83% are engaged in employment or petty business. About 56% are aware of prepayment mechanism for healthcare bills but only 10% of them have used prepayment mechanisms. Out of pocket payment (85%) is the main source of payment at health facilities. Major political constraining factors to UHC revealed by the IDI include lack of political will backed with financial commitment from the political leaders, lack of legislative framework for UHC, lack of trust on the political leaders/government by the citizenry and inactive civil society organizations. Also, the poor fiscal space for health and the poverty level in the populace are big threats to sustainable UHC in Enugu state. Other economic challenges include corruption, poor health capacity development and poorly paid healthcare workers leading to poor quality of health care delivery. There is need for comprehensive health system development in the state to accommodate UHC. Conclusions: Establishment of sustainable UHC in Enugu state faces considerable political and economic challenges. There is need for increased government budgetary allocation for UHC to ensure coverage for the poor and vulnerable members. The lack of legislative framework for UHC could be resolved by legislative arm of the government. The government should invest in health system development to improve the quality of health care services to compliment the FRP component of UHC. Keywords: Universal Health Coverage, Health Insurance, Financial Risk Protection DOI: 10.7176/DCS/9-4-07 Publication date: April 30th 201

Are there geographic and socio-economic differences in incidence, burden and prevention of malaria? A study in southeast Nigeria

<p>Abstract</p> <p>Rationale</p> <p>It is not clearly evident whether malaria affects the poor more although it has been argued that the poor bear a very high burden of the disease. This study explored the socioeconomic and geographic differences in incidence and burden of malaria as well as ownership of mosquito nets.</p> <p>Methods</p> <p>Structured questionnaires were used to collect information from 1657 respondents from rural and urban communities in southeast Nigeria on: incidence of malaria, number of days lost to malaria; actions to treat malaria and household ownership of insecticide treated and untreated mosquito nets. Data was compared across socio-economic status (SES) quartiles and between urban and rural dwellers.</p> <p>Results</p> <p>There was statistically significant urban-rural difference in malaria occurrence with malaria occurring more amongst urban dwellers. There was more reported occurrence of malaria amongst children and other adult household members in better-off SES groups compared to worse-off SES groups, but not amongst respondents. The average number of days that people delayed before seeking treatment was two days, and both adults and children were ill with malaria for about six days. Better-off SES quartile and urban dwellers owned more mosquito nets (p < 0.05) (treated and untreated).</p> <p>Conclusion</p> <p>Malaria occurs more amongst better-off SES groups and urban dwellers in southeast Nigeria. Deployment of malaria control interventions should ensure universal access since targeting the poor and other supposedly vulnerable groups may exclude people that really require malaria control services.</p

The NK cell checkpoint NKG2A maintains expansion capacity of human NK cells

Human natural killer (NK) cells are cytotoxic effector cells that are increasingly harnessed in cancer immunotherapy. NKG2A/CD94 is an inhibitory receptor on NK cells that has established regulatory functions in the direct interaction with target cells when engaged with its ligand, the non-classical HLA class I molecule HLA-E. Here, we confirmed NKG2A as a checkpoint molecule in primary human NK cells and identified a novel role for NKG2A in maintaining NK cell expansion capacity by dampening both proliferative activity and excessive activation-induced cell death. Maintenance of NK cell expansion capacity might contribute to the preferential accumulation of human NKG2A$^{+}$ NK cells after hematopoietic cell transplantation and enrichment of functionally impaired NK cells in human cancers. Functional silencing of NKG2A for cancer immunotherapy is highly attractive but will need to consider that this might also lead to a reduced survival by driving activation-induced cell death in targeted NK cells

The NK cell checkpoint NKG2A maintains expansion capacity of human NK cells

Human natural killer (NK) cells are cytotoxic effector cells that are increasingly harnessed in cancer immunotherapy. NKG2A/CD94 is an inhibitory receptor on NK cells that has established regulatory functions in the direct interaction with target cells when engaged with its ligand, the non-classical HLA class I molecule HLA-E. Here, we confirmed NKG2A as a checkpoint molecule in primary human NK cells and identified a novel role for NKG2A in maintaining NK cell expansion capacity by dampening both proliferative activity and excessive activation-induced cell death. Maintenance of NK cell expansion capacity might contribute to the preferential accumulation of human NKG2A⁺ NK cells after hematopoietic cell transplantation and enrichment of functionally impaired NK cells in human cancers. Functional silencing of NKG2A for cancer immunotherapy is highly attractive but will need to consider that this might also lead to a reduced survival by driving activation-induced cell death in targeted NK cells

Targeted adenovirus-mediated transduction of human T cells in vitro and in vivo

Clinical success in T cell therapy has stimulated widespread efforts to increase safety and potency and to extend this technology to solid tumors. Yet progress in cell therapy remains restricted by the limited payload capacity, specificity of target cell transduction, and transgenic gene expression efficiency of applied viral vectors. This renders complex reprogramming or direct in vivo applications difficult. Here, we developed a synergistic combination of trimeric adapter constructs enabling T cell-directed transduction by the human adenoviral vector serotype C5 in vitro and in vivo. Rationally chosen binding partners showed receptor-specific transduction of otherwise non-susceptible human T cells by exploiting activation stimuli. This platform remains compatible with high-capacity vectors for up to 37 kb DNA delivery, increasing payload capacity and safety because of the removal of all viral genes. Together, these findings provide a tool for targeted delivery of large payloads in T cells as a potential avenue to overcome current limitations of T cell therapy

Reduced frequency of cytotoxic CD56dim CD16+ NK cells leads to impaired antibody-dependent degranulation in EBV-positive classical Hodgkin lymphoma

Around 30–50% of classical Hodgkin lymphoma (cHL) cases in immunocompetent individuals from industrialized countries are associated with the B-lymphotropic Epstein-Barr virus (EBV). Although natural killer (NK) cells exhibit anti-viral and anti-tumoral functions, virtually nothing is known about quantitative and qualitative differences in NK cells in patients with EBV+ cHL vs. EBV- cHL. Here, we prospectively investigated 36 cHL patients without known immune suppression or overt immunodeficiency at diagnosis. All 10 EBV+ cHL patients and 25 out 26 EBV- cHL were seropositive for EBV antibodies, and EBV+ cHL patients presented with higher plasma EBV DNA levels compared to EBV- cHL patients. We show that the CD56dim CD16+ NK cell subset was decreased in frequency in EBV+ cHL patients compared to EBV- cHL patients. This quantitative deficiency translates into an impaired CD56dim NK cell mediated degranulation toward rituximab-coated HLA class 1 negative lymphoblastoid cells in EBV+ compared to EBV- cHL patients. We finally observed a trend to a decrease in the rituximab-associated degranulation and ADCC of in vitro expanded NK cells of EBV+ cHL compared to healthy controls. Our findings may impact on the design of adjunctive treatment targeting antibody-dependent cellular cytotoxicity in EBV+ cHL