Ineffective Immunity Research Articles

Engineered Carrier-Free Nanosystem-Induced In Situ Therapeutic Vaccines for Potent Cancer Immunotherapy.

In situ vaccines that can stimulate tumor immune response have emerged as a breakthrough in antitumor therapy. However, the immunosuppressed tumor microenvironment and insufficient infiltration of immune cells lead to ineffective antitumor immunity. Hence, a biomimetic carrier-free nanosystem (BCC) to induce synergistic phototherapy/chemotherapy-driven in situ vaccines was designed. A carrier-free nanosystem was developed using phototherapeutic reagents CyI and celastrol as raw materials. In vitro and in vivo studies have shown that under NIR light irradiation, BCC-mediated photo/chemotherapy not only accelerates the release of drugs to deeper parts of tumors, achieving timing and light-controlled drug delivery to result in cell apoptosis, but also effectively stimulates the antitumor response to induce in situ vaccine, which could invoke long-lasting antitumor immunity to inhibit tumor metastasis and eliminate distant tumor. This therapeutic strategy holds promise for priming robust innate and adaptive immune responses, arresting cancer progression, and inducing tumor dormancy.

A distinct stimulatory cDC1 subpopulation amplifies CD8+ Tcell responses in tumors for protective anti-cancer immunity.

Type 1 conventional dendritic cells (cDC1) can support Tcell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8+ Tcell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1+ stem-like CD8+ Tcells. We identify a distinct population of immunostimulatory CCR7neg cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8+ Tcell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7neg cDC1 interact with CD8+ Tcells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer Tcell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.

Immunity After Vaccination Against SARS-CoV-2 in Lung Transplant?

Introduction: SARS-CoV2 infection causes high morbidity and mortality in lung transplant recipients (LT). Vaccination with mRNA vaccines has been shown to play a key role in controlling the severity of infection in the general population. The aim of our study is to analyze whether vaccination with 2 doses of SARS-Cov2 provides immunity in LT.Material and Methods: Retrospective descriptive and analytical study of LTs vaccinated with 2 doses of SARS-CoV2. We analyzed the vaccine received, if they had COVID-19, antibody levels (anti-spike and anti-nucleoprotein), anticalcineurin levels, infections in the last year and the presence of neoplasias.Results: The most commonly administered vaccine was from the Moderna laboratory, with 27% of patients showing immunity with a median antibody levels of 4.81 BAU/ml far from the values considered protective (>34 BAU/ml). Thirteen patients were infected with SARS-CoV2, seven post-vaccination (five of them were anti-spike positive). No relationship was demonstrated between generation of immunity and age and level of immunosuppression.Conclusion: Vaccination against SARS-CoV2 in LT generates limited and ineffective immunity with only 2 doses.

Antigen Capture and Immune Modulation by Bacterial Outer Membrane Vesicles as In Situ Vaccine for Cancer Immunotherapy Post-Photothermal Therapy.

Tumor antigens released from tumor cells after local photothermal therapy (PTT) can activate the tumor-specific immune responses, which are critical for eliminating the residual lesions and distant metastases. However, the limited recognition efficiency of released tumor antigens by the immune system and the immunosuppressive microenvironment lead to ineffective antitumor immunity. Here, an in situ multifunctional vaccine based on bacterial outer membrane vesicles (OMVs, 1-MT@OMV-Mal) is developed by surface conjunction of maleimide groups (Mal) and interior loading with inhibitor of indoleamine 2, 3-dioxygenase (IDO), 1-methyl-tryptophan (1-MT). 1-MT@OMV-Mal can bind to the released tumor antigens after PTT, and be efficiently recognized and taken up by dendritic cells. Furthermore, in situ injection of 1-MT@OMV-Mal simultaneously overcomes the immune inhibition of IDO on tumor-infiltrating effector T cells, leading to remarkable inhibition on both primary and distant tumors. Together, a promising in situ vaccine based on OMVs to facilitate immune-mediated tumor clearance after PTT through orchestrating antigen capture and immune modulation is presented.

Clinical and Immunological Assessment of Patients with Sars-Cov-2 Infections

▪Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced coronavirus disease-2019 (COVID-19) has presented humanity with unprecedented challenges. Severe disease is associated with acute respiratory distress syndrome (ARDS), use of mechanical ventilation, ICU stay and prolonged hospitalization, The role of the immune system in the pathogenesis of COVID-19 disease is still unclear, which imposes limitations on identifying potential immunotherapy that can improve care for acute and chronic phases of COVID-19 in conjunction with current therapies. Research efforts are ongoing for more than 1 year to identify key immunological mechanisms involved in the disease process. While insightful, this knowledge is still incomplete and can be complemented with the assessment of immune response kinetics. Such assessment will help with the identification of early interventional modalities of immune cell regulation. With these considerations in mind, we aimed to assess several parameters of immune system regulation during the current medical care of patients with COVID-19.Methods: This is a pre-clinical prospective cohort study which involved laboratory-based assessments of blood samples obtained from COVID-19 patients and healthy volunteers. The study population was divided into three cohorts. Our first cohort included 18 years and older COVID-19 patients with respiratory complaints, oxygen (O2) saturations of less than or equal to 92 and pulmonary infiltrates on an imaging study or who were critically ill and required ventilatory support. Second cohort included 18 years and older COVID-19 patients who were hospitalized and did not require ventilatory support. Third cohort included participants with no prior diagnosis of COVID-19, or any recent viral respiratory symptoms including fever, cough or shortness of breath for the last 2 weeks. Patients with an established diagnosis of cancer or immunologic disorders were excluded. Blood specimens were collected over the period of hospitalization: specimen number 1 on day 1-3 of hospitalization, specimen number 2 on days 3-4 of hospitalization, specimen number 3 on days 5-7 of hospitalization, and specimen number 4 on 7-30 days after discharge. We performed capillary electrophoresis for serology and automated ELISA for cytokine measurement. We collected clinical data on patient demographic, clinical characteristics such as presence of any acute and chronic comorbidities and serum inflammatory markers C-Reactive Protein, D-Dimer and Ferritin.Results: We had 15 patients in cohort 1, 10 in cohort 2 and 15 in cohort 3. Patients in cohort 1 were older and had higher comorbidities. Males constituted a substantially high percentage of patients in cohort 1 and 2 (60% and 70% respectively). Patients had similar BMI in cohort 1 and 2. Total antibody levels were highest in cohort 1 but an upward trend over the course of hospitalization was noted in all cohorts. Most interesting pattern was noted in the context of antibodies against spike protein S1 receptor-binding domain (S1RBD) where patients in cohort 2 developed minimal S1RBD antibodies. Cohort 1 on average had higher levels of Interleukin 6(IL-6), Interleukin 8(IL-8), C-X-C motif chemokine ligand 10 (CXCL10) and other inflammatory cytokines except Interferon gamma (IFN-gamma) compared to Cohort 2. Remarkable difference in CXCL-10 levels was noted between the groups and healthy volunteers had the lowest levels. No significant difference in IFN-gamma was noted between cohorts and the levels quickly depleted over the course of the infection.Conclusion: Our analysis confirms that neutralizing antibodies do not correlate with lessened COVID-19 disease severity. Severe COVID-19 infection is secondary to ineffective innate immunity associated with immune overshoot. CXCL10 serves as a major component in triggering the cytokine storm that is a hallmark of SARS-CoV-2 infections. Our findings show an association between high levels of CXCL10 and more severe COVID-19 infection. There does not seem to be any significant correlation with disease severity and IFN-gamma levels. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The five axes of COVID-19 treatment: attacking the disease from several angles.

The emergency situation of the COVID-19 pandemics requires immediate action. As happens with emerging pathogens, there are no specific treatments for this threat, so that the most logical answer in order to find safe and effective candidates seems to be drug repurposing. The main efforts in finding a specific treatment for this disease have been directed to finding antiviral agents, nonetheless, COVID-19 also involves lung and systemic inflammation, coupled with ineffective immunity; bacterial and fungal coinfections; respiratory dysfunction; and coagulopathy. These additional pathophysiologic axes also require a set of treatments, and in this review we will analyze such adjunctive therapies.

NEUROCRYPTOCOCOSIS:

INTRODUCTION Composed of about 30 species, the genus Cryptococcus has two species of greater clinical relevance in humans, C. neoformans and C.gattii. The first one was not considered a high morbidity species, initially, but in the 1980s, with the institution of the human immunodeficiency virus (HIV), this scenario changed. Since then it has come to be considered the most life-threatening ringworm for patients living with HIV, accounting for about 625,000 deaths annually. OBJECTIVE To determine the main points of neurocriptococcosis in the population with HIV. METHODOLOGY The search for the articles was carried out in the MEDLINE/ PUBMED and BVS databases. The descriptors used were chosen on the BIREME platform in Portuguese and English, and were respectively: Meningitis, Cryptococcal; Acquired Immunodeficiency Syndrome; Diagnosis; Therapeutics; Signs and Symptoms. Other texts were chosen during the course of reading the articles in the databases, according to the bibliographic references. In total, 35 articles were selected to compose this narrative review. DEVELOPMENT Cryptococcosis is more prevalent in urban areas of countries with tropical and subtropical climates. The fungus in question is found in pigeon droppings and the infection occurs by inhalation. Such yeast has tropism for the central nervous system due mainly to ineffective immunity. High morbidity, above all, occurs in patients with a TCD4 cell count below 100/mL, seen in HIV-positive patients. FINAL CONSIDERATIONS Cryptococcosis is the pathology with the highest prevalence in the population with HIV and the one that confers the highest morbidity in this group. It reveals a plural clinic, with neurocriptococcosis being the first opportunistic manifestation in this group. Mortality rates are high and uneven between developed and underdeveloped countries, including those directly related to the choice of initial therapy.

The Analysis of Scientific Data on the Efficacy of Pneumococcal Conjugated Vaccine in the Cohort of Children with Bronchial Asthma

This article refutes one popular-science review that has appeared on the MDedge news site in January 2020. It has stated that there was no effect of vaccination with 7-valent pneumococcal conjugate vaccine (PCV-7) against invasive forms of Streptococcus pneumoniae in children with bronchial asthma. The author of this publication refers to the article «Asthma and the Risk of Invasive Pneumococcal Disease: A Meta-analysis» that described episodes of invasive pneumococcal disease and pneumonia development in children with bronchial asthma and in healthy children who was vaccinated with pneumococcal conjugate vaccine. It was concluded that the PCV-7 provides limited protection against colonization only with vaccine pneumococcus serotypes (according to the obtained data), and, thus, there was high risk of carriage of non-included serotypes in children with bronchial asthma (BA). The analysis of the article mentioned above has revealed that the representativeness of the data is extremely low. For example, the study groups were selected incorrectly, the PCV-7 administration scheme was not analyzed, whereas its violation may cause ineffective immunity development and as result disease development. Another crucial aspect is the lack of any data on the BA severity and inhaled corticosteroid therapy in vaccinated children. Nowadays, there are numerous scientific studies on the clinical efficacy of PCV in the prevention of IPD including the children with BA. Most world-class experts support the necessity of PCV-7 usage in children with BA for the prevention of IPD and suggest their patients over 6 years old on inhaled corticosteroid therapy to perform additional administration of pneumococcal polysaccharide vaccine.

Immunologic Predictors for Clinical Responses in Patients with Myelodysplastic Syndromes Treated with Immune Checkpoint Blockade

Immunologic Predictors for Clinical Responses in Patients with Myelodysplastic Syndromes Treated with Immune Checkpoint Blockade

The five axes of COVID-19 treatment: attacking the disease from several angles.

The emergency situation of the COVID-19 pandemics requires immediate action. As happens with emerging pathogens, there are no specific treatments for this threat, so that the most logical answer in order to find safe and effective candidates seems to be drug repurposing. The main efforts in finding a specific treatment for this disease have been directed to finding antiviral agents, nonetheless, COVID-19 also involves lung and systemic inflammation, coupled with ineffective immunity; bacterial and fungal coinfections; respiratory dysfunction; and coagulopathy. These additional pathophysiologic axes also require a set of treatments, and in this review we will analyze such adjunctive therapies.

A Framework for Understanding the Evasion of Host Immunity by Candida Biofilms.

Candida biofilms are a major cause of nosocomial morbidity and mortality. The mechanism by which Candida biofilms evade the immune system remains unknown. In this perspective, we develop a theoretical framework of the three, not mutually exclusive, models, which could explain biofilm evasion of host immunity. First, biofilms may exhibit properties of immunological silence, preventing immune activation. Second, biofilms may produce immune-deviating factors, converting effective immunity into ineffective immunity. Third, biofilms may resist host immunity, which would otherwise be effective. Using a murine subcutaneous biofilm model, we found that mice infected with biofilms developed sterilizing immunity effective when challenged with yeast form Candida. Despite the induction of effective anti-Candida immunity, no spontaneous clearance of the biofilm was observed. These results support the immune resistance model of biofilm immune evasion and demonstrate an asymmetric relationship between the host and biofilms, with biofilms eliciting effective immune responses yet being resistant to immunological clearance.

Swine enteric coronavirus disease: A review of 4years with porcine epidemic diarrhoea virus and porcine deltacoronavirus in the United States and Canada.

SummarySwine enteric coronaviruses, including porcine epidemic diarrhoea virus (PEDV) and porcine deltacoronavirus (PDCoV), have emerged and spread throughout the North American swine industry over the last four years. These diseases cause significant losses within the pork industry and within the first year after PEDV introduction, approximately 10% of the US herd died due to the disease. Similar to other enteric coronaviruses, such as transmissible gastroenteritis virus (TGEV), these emerging swine enteric coronavirus diseases (SECD) are age‐dependent, with high morbidity and mortality in neonatal pigs. Since the introduction of SECD, research has focused on investigating viral pathogenesis through experimental inoculation, increasing maternal antibody for neonatal protection, understanding transmission risks through feed and transportation, and outlining the importance of biosecurity in preventing SECD introduction and spread. A survey of swine professionals conducted for this review revealed that the majority of respondents (75%) believe SECD can be eradicated and that most herds have been successful at long‐term elimination of SECD after exposure (80%). However, unique properties of SECD, such as ineffective immunity through parenteral vaccination and a low oral infectious dose, play a major role in management of SECD. This review serves to describe the current knowledge of SECD and the characteristics of these viruses which provide both opportunities and challenges for long‐term disease control and potential eradication from the US swine population.

BscF from Bordetella pertussis provides advantageous adjuvant activity when paired with the acellular pertussis vaccine: enhanced Th1/Th17 pertussis-specific immune response

Abstract Incidence of pertussis, a severe respiratory disease caused by Bordetella pertussis, have been on the rise. This resurgence has been linked to antigenic divergence in circulating pertussis strains as well as waning or ineffective immunity induced by the current acellular pertussis (aP) vaccine. The current aP vaccine replaced a whole cell pertussis (wP) vaccine in the 1990s due to adverse events associated with the wP vaccine. Alum-absorbed aP vaccine has been shown to elicit a strong antibody response and considerable Th2 type CD4+ T cells. In contrast, wP vaccine promotes Th1/Th17 type cellular immunity and associated opsonizing antibodies presumably via its PAMPs. We have previously demonstrated that BscF, a B. pertussis needle protein, acts as a strong TLR agonist. Here we characterized the contribution of BscF to a laboratory prepared aP vaccine-induced response. aP + BscF resulted in statistically greater pertussis-specific antibody titers, compared to sham aP + PBS. BscF enhanced long-term aP-specific immunity, compared to either the alum or sham controls, as measured by increased numbers of central memory T cells. Moreover, the addition of BscF resulted in skewing the pertussis-specific immunity toward Th1 and Th17 responses, compared to the addition of alum or PBS which skewed pertussis-specific immunity away from Th1/Th17 responses. Mice immunized with aP + BscF demonstrated significantly reduced bacterial burden in their lungs 5 dpi. These findings suggest that BscF induced a strong Th1 and Th17 anti-pertussis response, potentially may provide protective BscF-specific immunity, and could be a novel additional component in the next generation aP vaccine.

Unique microRNAs appear at different times during the course of a delayed-type hypersensitivity reaction in human skin.

Diphencyprone (DPCP) is a hapten that induces delayed-type hypersensitivity (DTH) reactions. MicroRNAs (miRNAs) are short non-coding RNAs that negatively regulate gene expression and have been implicated in various inflammatory skin diseases, but their role in DTH reactions is not well understood. We generated global miRNA expression profiles (using next-generation sequencing) of DPCP reactions in skin of seven healthy volunteers at 3, 14 and 120 days after challenge. Compared to placebo-treated sites, DPCP-challenged skin at 3 days (peak inflammation) had 127 miRNAs significantly deregulated. At 14 days (during resolution of inflammation), 43 miRNAs were deregulated and, at 120 days (when inflammation had completely resolved), six miRNAs were upregulated. While some miRNAs have been observed in psoriasis or atopic dermatitis, most of the deregulated miRNAs have not yet been studied in the context of skin biology or immunology. Across the three time points studied, many but not all miRNAs were uniquely expressed. As various miRNAs may influence T cell activation, this may indicate that the miRNAs exclusively expressed at different time points function to promote or resolve skin inflammation, and therefore, may inform on the paradoxical ability of DPCP to treat both autoimmune conditions (alopecia areata) and conditions of ineffective immunity (melanoma).

Host Immunological Factors Enhancing Mortality of Young Adults during the 1918 Influenza Pandemic

During the 1918 influenza pandemic, healthy young adults unusually succumbed to infection and were considered more vulnerable than young children and the elderly. The pathogenesis of this pandemic in the young adult population remains poorly understood. As this population is normally the least likely to die during seasonal influenza outbreaks, thought to be due to their appropriate pre-existing and robust immune responses protecting them from infection, we sought to review existing literature for immunological reasons for excessive mortality during the 1918 pandemic. We propose the novelty of the H1N1 pandemic virus to an H1N1 naïve immune system, the virulence of this virus, and dysfunctional host inflammatory and immunological responses, shaped by past influenza infections could have each contributed to their overall susceptibility. Additionally, in the young adult population, pre-exposure to past influenza infection of different subtypes, such as a H3N8 virus, during their infancy in 1889–1892, may have shaped immunological responses and enhanced vulnerability via humoral immunity effects with cross-reactive or non-neutralizing antibodies; excessive and/or ineffective cellular immunity from memory T lymphocytes; and innate dysfunctional inflammation. Multiple mechanisms likely contributed to the increased young adult mortality in 1918 and are the focus of this review.

BscF as a vaccine candidate for Bordetella pertussis infection (“Whooping Cough”) (VAC9P.1064)

Abstract Bordetella pertussis, a Gram- bacterium, causes pertussis (“Whopping Cough”). Despite widespread vaccination, 48 million cases of pertussis occur annually worldwide. The resurgence of pertussis is linked to antigenic divergence of circulating pertussis and waning and/or ineffective immunity induced by the current acellular vaccine. YscF, a Yersinia protein that, in multimeric form, makes up the Type III Secretion System (T3SS) needle, has been shown to be both an excellent protective antigen for Y. pestis, as well as a strong adjuvant via TLR signaling. We characterized here immune responses induced by BscF, the Bordetella homolog of YscF. BscF activated NF-κB through both TLR-2 and TLR-4 in vitro. Moreover, BscF induced IL-1β and IL-12 secretion in human THP-1 cells and bone marrow-derived macrophages. In vivo, BscF immunization in alum induced both a Th1 and Th17 response, with stimulated CD4+ T cell secreting both IFN-γ and IL-17A. Interestingly, in vivo BscF (in alum) also induced significant titers of BscF-specific antibody of all IgG isotypes (1, 2a, 2b, 3), suggesting the induction of both Th1 and Th2 responses. In toto we demonstrated that BscF induces a strong humoral and cell-mediated protein-specific immune response. This, along with the adjuvant characteristic and external structural location of BscF, suggests that BscF may provide an excellent addition to the current acellular vaccine to yield a stronger and/or more persisted protection against pertussis.

Improved pertussis vaccines based on adjuvants that induce cell-mediated immunity

Bordetella pertussis is a Gram-negative bacterium that causes the severe and sometimes lethal respiratory disease whooping cough in infants and children. There has been a recent resurgence in the number of cases of pertussis in several countries with high vaccine coverage. This has been linked with waning or ineffective immunity induced by current acellular pertussis vaccines. These acellular pertussis vaccines are formulated with alum as the adjuvant, which promotes strong antibody responses but is less effective at inducing Th1-type responses crucial for effective bacterial clearance. Studies in animal models have demonstrated that replacing alum with alternative adjuvants, such as toll-like receptor agonists, can promote more robust cell-mediated immunity and confer a high level of protection against infection following respiratory challenge.

Hemophagocytic lymphohistiocytosis: review of etiologies and management.

Hemophagocytic lymphohistiocytosis (HLH) covers a wide array of related life-threatening conditions featuring ineffective immunity characterized by an uncontrolled hyperinflammatory response. HLH is often triggered by infection. Familial forms result from genetic defects in natural killer cells and cytotoxic T-cells, typically affecting perforin and intracellular vesicles. HLH is likely under-recognized, which contributes to its high morbidity and mortality. Early recognition is crucial for any reasonable attempt at curative therapy to be made. Current treatment regimens include immunosuppression, immune modulation, chemotherapy, and biological response modification, followed by hematopoietic stem-cell transplant (bone marrow transplant). A number of recent studies have contributed to the understanding of HLH pathophysiology, leading to alternate treatment options; however, much work remains to raise awareness and improve the high morbidity and mortality of these complex conditions.

Comparative Analysis of Immune Responses in Pigs to High and Low Pathogenic Porcine Reproductive and Respiratory Syndrome Viruses Isolated in China

The CH-1a and HuN4 strains of porcine reproductive and respiratory syndrome virus (PRRSV) show different pathogenicities in pigs. To understand host immune responses against these viruses, we investigated the dynamic changes in cytokine levels produced in peripheral blood of piglets infected with the highly pathogenic PRRSV HuN4 strain or the CH-1a strain. Clinical signs, virus loads and serum cytokine levels [interferon(IFN)-α, Interleukin (IL)-1, TNF-α, IL-6, IL-12, IFN-γ, IL-10 and TGF-β] were tested. The results showed that while piglets developed effective cellular immune responses against CH-1a infection, those infected with HuN4 displayed ineffective cellular immunity, organ lesions and persistent elevated levels of immunoregulatory cytokines (IL-10 and TGF-β), which delayed the development of PRRSV-specific immune responses. These results demonstrated that HuN4 infection induced higher cytokine levels than that of CH-1a infection induced. The changes in inflammatory cytokines intensified the inflammatory reaction and damaged the tissues and organs.

Understanding Respiratory Syncytial Virus Infection to Improve Treatment and Immunity

Despite significant research since it was discovered more than 50 years ago, respiratory syncytial virus (RSV) continues to be the leading agent causing infant hospitalization and respiratory distress worldwide. Although RSV normally does not cause mortality, this virus is recognized as a major public health and economic burden around the globe. RSV can modulate host immunity leading to an inflammatory response that produces lung damage and virus dissemination in the host airways. Remarkably, infection with the virus elicits poor immunity that in most cases fails to protect against subsequent exposures. Here, we review advances made on the understanding of the lifecycle of the virus, some of the molecular mechanisms it has evolved to cause pathology and ineffective immunity during infection. Hopefully, ongoing research will contribute to developing new drugs and candidate vaccines that will decrease the health burden caused by this virus.