Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

BackgroundThe powerful ‘graft versus leukemia’ effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease.MethodsWe report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML).ResultsIn this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment.ConclusionAddition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.

Healing through faith: meeting a chaplain coupled with biblical readings could produce lymphocyte changes that correlate with brain activity (HEALING study)

Introduction: Faith and systems of beliefs are known to impact not only the emotional, but also the immunological state of believers in ways that we are just starting to understand. Moreover, clinical implications of previous studies are limited. The aim of the “HEALING” (Hospital-based Ecumenical and Linguistic Immuno-NeuroloGic) Study was to examine immunological and neurological changes in hospitalized patients after meeting a chaplain coupled with biblical readings. Methods: Hospitalized patients were pre-screened to find those who were the most in need of an intervention. A passage from the Bible was read to them during a meeting with the chaplain at the bedside (n= 20) or in the chapel (n= 18). No meeting occurred in the randomized control group (n=19). Blood samples were taken 30 minutes prior, and 60 minutes after the meeting to measure white blood cells (WBC), interferon gamma (IFN-γ), immunoglobulin M (IgM), IgA, IgG, and complement 3 (C3). A subgroup of the visited patients was subjected to functional magnetic resonance imaging (fMRI), where they were played an audiotape of readings of the same passage from the Bible (n=21). Results: Lymphocyte counts increased more often after the more successful visits, but the immunological changes were not significant. Conversely, a significant (pfwe=0.003) correlation was revealed between changes in lymphocytes and activation of the angular gyrus (left BA39) during fMRI, a brain area involved in word recognition. Conclusions: Although limited by the sample size and cohort study design, the findings suggest the depth of psycho-immunological changes could depend on the degree to which the chaplains’ main message is understood.

Allergen-Specific IgE and IgG4 as Biomarkers for Immunologic Changes during Subcutaneous Allergen Immunotherapy

(1) Background: Biomarkers of efficacy for subcutaneous immunotherapy (SCIT) on allergic rhinitis have not been evaluated in details. The present study aims to assess the relevance of measuring of sIgE, sIgG4 and IgE/IgG4 ratio during SCIT in patients with allergic rhinitis; (2) Methods: 20 patients, 13 men and 7 women aged 19 to 58 years, with clinically manifested seasonal and perennial allergic rhinitis were studied. At the initiation and in the end of the three-year course of SCIT serum allergen-specific IgE and IgG4 were measured with ImmunoCAP system. The sIgE/sIgG4 ratio was calculated as a biomarker for immunologic effectiveness; (3) Results: There was a significant increase of sIgG4 antibodies (p < 0.05), while at the end of SCIT for the sIgE levels no significant changes were seen (p > 0.05). Moreover, 90% of patients showed a decrease of the IgE/IgG4 ratio; (4) Conclusions: In most of treated patients with AR, SCIT with Bulgarian allergen products leads to clear immunological changes. After a 3-year of SCIT there is a significant increase in allergen specific IgG4 levels and both decrease of sIgE and IgE/IgG4 ratio. sIgE, sIgG4 and IgE/IgG4 ratio can be used as a substantial biomarker for predicting immunological effectiveness of SCIT.

Eczema herpeticum subsequent to septic shock in early pregnancy: a first case report

Background Eczema herpeticum (EH) is a severe skin complication caused by human simplex virus (HSV) infection concomitant with immune dysfunction and dermatological conditions, mainly atopic dermatitis. We present the first case of EH subsequent to sepsis-related immunological suppression in pregnancy. Case presentation Septic shock developed in a 30-year-old primiparous woman at 14 weeks of pregnancy during admission for hyperemesis gravidarum. Although her life-threatening status due to sepsis improved by prompt treatment, on day 3 of treatment in the intensive care unit, blisters suddenly erupted on her face and neck and spread over her body. EH was diagnosed according to HSV type-1 antigen positivity and a past medical history of EH and atopic dermatitis. Antiviral agents were administered immediately, with positive results. Her general condition improved quickly, without central nervous system defects. This is the first report of EH following septic shock in early pregnancy. At present, we speculate that EH develops as a complication due to immunological changes in the late phase of sepsis because sepsis is mainly characterized by both an inflammatory state in the acute phase and an immunosuppressive state in the late phase. Pregnancy can also contribute to its pathogenesis, as it causes an immunosuppressive state. Mortality due to EH is relatively high; in this case, a history of EH and atopic dermatitis contributed to the initiation of prompt medical interventions for the former, with improvement in the patient’s severe condition. The combination of immunological changes in sepsis and pregnancy can cause HSV reactivation, resulting in EH recurrence. Conclusions In conclusion, if dermatological symptoms develop in a pregnant woman with a history of EH and/or atopic dermatitis treated for sepsis, EH should be suspected based not only on clinical features but also on immunological changes along with sepsis, and prompt medical interventions should be initiated.

Pathogenetic justification of the use of criteria for determining the lifespan and age of wound caused by mechanical damage

The aim of the study is detailed analysis of the literature on the existing methods for determining the lifetime and inflicting of mechanical damage. It was found that the existing methods have very large discrepancies in assessing the infliction of damage. The use of the same research methods by different researchers has lead to results that may differ. This can lead to obtaining insufficiently substantiated or even erroneous conclusions about the infliction of mechanical damage. The authors explain this by the fact that the body reacts to damage by the development of a typical pathological process – inflammation. Forensic methods that exist for determining the age of wound are aimed at obtaining an expert assessment of individual manifestations of the pathogenesis of inflammation by morphological, biochemical and immunological methods. Determination of the age of wound is actually the determination of a specific stage in the pathogenesis of inflammation, which is observed at the time of the examination and the timing of the development, which is known from the literature. Taking into account the stages of the pathogenesis of inflammation as a typical pathological process, in the area of tissue damage makes it possible to more accurately determine the duration of the infliction of mechanical damage. The individual reactivity of the organism, which determines the features of the course of any typical pathological process, will determine the individual timing of the development of certain morphological, biochemical and immunological changes in the area of damage.

65 Immunological Changes in Response to Treatment of Bovine Respiratory Disease in Newly Received Commercial Stocker Calves

Immunological changes in stocker calves treated for Bovine Respiratory Disease (BRD) could indicate disease progression or treatment success. Our objective was to determine the changes in immune parameters in stocker calves in response to the number of treatments they received for BRD. Forty newly weaned crossbred beef steers purchased from the auction market were kept at a commercial stocker operation at Crossville during winter 2020. Calves were monitored for 4wks and blood samples were collected on days 0, 7, 14, and 21. All calves were assigned a clinical severity scoring (CSS; 0: normal, 3: moribund) on each sampling day. Antibiotic treatment was assigned when calves were categorized as having BRD based on CSS and rectal temperature. Immune parameters (Haptoglobin, IL-8, IL-1β, and TNFα) were determined using commercial ELISA kits. Calves were categorized based on the cumulative number of treatments received by the end of study period (0x, 1x, and ≥2x). Proc GLIMMIX (SAS 9.4) was used to test the fixed effects of treatment number, day of treatment, and their interaction, accounting for day as a repeated measure. To achieve the normality of residuals, log transformation was performed. Significance was determined at α= 0.05. The incidence of BRD was 40% (16 out of 40). Haptoglobin concentration was higher (P = 0.02) in ≥2x (1.85 ± 0.30 mg/mL) compared to 0x (0.74 ± 0.21 mg/mL). A treatment by day interaction (P = 0.03) was observed for IL-8. On day 14, calves that were treated ≥2x times had higher IL-8 compared to the rest of the statuses; no differences were observed for other days between statuses. The lowest IL-1β (P = 0.04) and TNFα (P = 0.001) concentrations were observed on day 0. Results from this study provide an overview of the immunological changes occurring in BRD-affected stocker calves requiring different treatment numbers.

Imbalanced Immune Response of T-Cell and B-Cell Subsets in Patients with Moderate and Severe COVID-19

Background: The immunological changes associated with COVID-19 are largely unknown. Methods: Patients with COVID-19 showing moderate (n = 18; SpO2 > 93%, respiratory rate > 22 per minute, CRP > 10 mg/L) and severe (n = 23; SpO2 < 93%, respiratory rate >30 per minute, PaO2/FiO2 ≤ 300 mmHg, permanent oxygen therapy, qSOFA > 2) infection, and 37 healthy donors (HD) were enrolled. Circulating T- and B-cell subsets were analyzed by flow cytometry. Results: CD4+Th cells were skewed toward Th2-like phenotypes within CD45RA+CD62L− (CM) and CD45RA–CD62L− (EM) cells in patients with severe COVID-19, while CM CCR6+ Th17-like cells were decreased if compared with HD. Within CM Th17-like cells “classical” Th17-like cells were increased and Th17.1-like cells were decreased in severe COVID-19 cases. Circulating CM follicular Th-like (Tfh) cells were decreased in all COVID-19 patients, and Tfh17-like cells represented the most predominant subset in severe COVID-19 cases. Both groups of patients showed increased levels of IgD-CD38++ B cells, while the levels of IgD+CD38− and IgD–CD38− were decreased. The frequency of IgD+CD27+ and IgD–CD27+ B cells was significantly reduced in severe COVID-19 cases. Conclusions: We showed an imbalance within almost all circulating memory Th subsets during acute COVID-19 and showed that altered Tfh polarization led to a dysregulated humoral immune response.

Effect of ORF7 of SARS-CoV-2 on the Chemotaxis of Monocytes and Neutrophils In Vitro

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threat worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis Transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.

Effect of ORF7 of SARS-CoV-2 on the chemotaxis of monocytes and neutrophils in vitro

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threats in worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.