Cellular Immune Activity Research Articles

Severe Ketoacidosis as the First Clinical Manifestation of Type 1 Diabetes Mellitus Secondary to Immune Checkpoint Inhibitors

Introduction Immunotherapy represents one of the fundamental points on the oncological treatments. The increasingly frequent use of these treatments has allowed us to observe various side effects in up to 10 to 20% of patients and endocrine side effects are one of the most commonly described. We report a case of diabetic ketoacidosis in a 46-year-old male patient as debut of type-1 diabetes mellitus secondary to treatment with nivolumab. Case Report The patient who went to the emergency department due to abdominal pain associated with vomiting 48 hours previously. Diagnosed 4 years ago of clear cell renal carcinoma stage IV, due to pulmonary metastatic involvement, the patient was under treatment with nivolumab. Urgent blood and urine tests were performed in the urgency evaluation; the patient was diagnosis of severe diabetic ketoacidosis. Pancreatic endocrine complications are observed in 0.5 to 5% of the patients with immunotherapy. Among the adverse effects described are alterations in baseline fasting glycaemia and the possible development of type-1 diabetes. These molecules increase the activity of T-cells, amplify the cellular immune activity with the consequent increased immune response, which can lead to a destruction of the pancreatic β-cells. Strict endocrine control is necessary during immunotherapy treatment; however, there are no clear indications for the monitoring of pancreatic reserve levels or glycemic control. For these reasons, we propose the need for closer and regular monitoring of C-peptide and HbA1c (glycosylated hemoglobin) to prevent the development of the diabetes and their complications.

IDO1+ Paneth cells promote immune escape of colorectal cancer

Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy.

Clinical and laboratory portraits of patients with tuberculosis and alcohol consumption

The aim was to study the clinical and laboratory data of patients with firstly diagnosed pulmonary tuberculosis with different levels of alcohol consumption.Materials and methods. The study included 102 patients with firstly diagnosed pulmonary tuberculosis and preserved sensitivity to anti-TB drugs with alcohol consume. The activity of gamma-glutamyltranspeptidase was determined by the kinetic method. C-reactive protein levels were determined by latex agglutination. To analyse the parameters of the quality of life the SF-36 questionnaire was used. Assessment of the alcohol consumption level was carried out using the Alcohol Use Disorders Identification Test. The obtained data were processed using the Statistica software.The results. According to the results of the AUDIT questionnaire, patients were divided into three groups. Group 1 – persons who scored 0–7 points, group 2 – 8–15 points, group 3 – 16 points or more. The quality of life in the first two groups were at a fairly high level with a predominance of the physical component of health. In the third group, the average indicators for both components were significantly lower than the first two groups. Group 3 patients were more socially maladaptive. In the group of alcohol-abusing patients, pathological process predominant affecting more than one lobe of the lungs with signs of destructive processes of the lung tissue. In 82.1 % of patients in group 3 mycobacterium tuberculosis was detected in sputum already at the stage of microscopic examination. In tuberculosis patients with increasing of alcohol consumption, there was an increase the blood levels of leukocytes, CRP and ESR, manifestations of anemia and a decrease in the activity of cellular immunity due to a decrease of lymphocytes degree. Maximum disturbances occurred in group 3. Indicators of the functional state of the liver, except for ALT, in group 3 were significantly higher than in group 1.Conclusions. Patients with tuberculosis who consume alcohol, has a decrease in social adaptation, quality of life, the more clearly intoxication syndrome, the prevalence of spreading forms of tuberculosis with massive bacterial excretion, as well as impaired liver function

PDL1-targeted vaccine exhibits potent antitumor activity by simultaneously blocking PD1/PDL1 pathway and activating PDL1-specific immune responses.

Despite the clinical success of immune checkpoint blockade, only a subset of people exhibits durable responses, suggesting that an alternative immunotherapeutic strategy is required. This paper reported a two-in-one cancer vaccine that targets programmed death ligand 1 (PDL1) that blocks the PD1/PDL1 pathway and also activates antitumor immune response. The PDL1- NitraTh vaccine, which consists of the extracellular domain of PDL1 and nitrated T cell epitope, effectively broke the immune tolerance of PDL1 and elicited PDL1-specific humoral and cellular immunity. The treatment of PDL1-NitraTh exhibited potent antitumor activity. Moreover, immunization of PDL1 vaccine increased the infiltration of tumor lymphocytes and decreased the proportion of Treg cells in tumor tissues, suggesting that the vaccine may remodel the tumor microenvironment. The upregulation of PDL1 in tumor tissues was induced by PDL1-NitraTh vaccine but not in spleen and lymphomas. This upregulation of PDL1 is beneficial to the antitumor activity of PDL1-specific humoral and cellular immunity induced by PDL1-NitraTh. In summary, PDL1-targeted vaccine exhibits potent antitumor activity and may provide an alternative immunotherapy strategy for patients who are not sensitive to PDL1 antibody drugs.

Влияние умеренно гипоксической среды среднегорья и дозированных физических нагрузок на укрепление иммунитета у детей с РАС

The cross-over effect of the influence of the hypoxic environment and physical activity, designated as “cross-adaptation”, on the health promotion of children with autism spectrum disorders (ASD) was investigated. A model has been developed for correcting the health of children with ASD on the basis of systematic seasonal 10-day physical training courses in a natural moderately hypoxic environment. Systematic health improvement courses with the use of special physical exercises in conditions of natural mountain hypoxia develop cellular and humoral mechanisms of immune responses, increase immunity, improve the physical and psycho-emotional state of children. Among 50 young and adolescent children diagnosed with ASD, after 4 10-day health improvement courses during the year, 20% of young children and 80% of adolescents showed an increase in the activity of cellular and humoral immunity. The proposed model for correcting the health of children with ASD is a promising universal non-drug way to increase immunity, stimulate the processes of adaptation and socialization of children with ASD. In the opinion of parents, after health improvement courses, many children have a desire to communicate with both parents and other children.

Metallothionein, hemocyte status and superoxide dismutase/aspartate aminotransferase activity are sensitive biomarkers of cadmium stress in Onchidium reevesii

Metal pollution in the environment is a serious threat to the biological sustainability of coastal ecosystems. However, our current understanding of the biological effects of metals in these ecosystems is limited. Herein, we investigated the responses of the sea slug Onchidium reevesii to persistent sublethal Cd environmental stress. Dynamic expression was analyzed using various biomarkers. The full-length cDNA of O. reevesii metallothionein (MT) was cloned and consists of 1639 nucleotides encoding a 65 amino acid polypeptide. Phylogenetic analysis showed that Or-MT has conserved Cys residues typical of MTs, including a typical Cys–X–Cys motif, implying that it can function the same as the MT of other shellfish. Expression of Or-MT in response to Cd varied in different tissues, and was highest in gastropod tissues. Thus, regiotemporal expression of MT may be useful for assessing pollution in coastal areas. Cellular immunity (in the hemolymph) and enzyme activity (in the hepatopancreas) were investigated along with hemocyte viability, hemocyte phagocytosis, and superoxide dismutase (SOD) and aspartate aminotransferase (AST) activities. Hemocyte viability was elevated under continuous Cd exposure but hemocyte phagocytosis was decreased. SOD and AST activities in the hepatopancreas fluctuated considerably, and SOD activity was more sensitive. SOD activity was lowest at 4 h and highest at 12 h, while AST activity peaked at 2 h and was lowest at 48 h. Thus, changes in enzyme activity may reveal adaptation to stress. Furthermore, the response patterns of certain enzymes, cellular immunity, and MT expression in O. reevesii could serve as biomarkers of Cd pollution in aquatic environments.

Abstract 152: Gene expression and mutational load in colon tumors from African American patients

Abstract Colorectal cancer (CRC) is the third most common cancer among African Americans (AA) and when compared to Caucasian Americans (CA), they present with more advanced disease and lower survival rates. Our previous findings suggest that this may be related to the differential expression of genes linked to cell recruitment and immune response. Therefore, we aimed to investigate if differences in the cellular anti-tumor immune activity in AA and CA patients play a role in the disparate cancer progression observed between these populations. Our approach includes examining gene expression and immune cell recruitment at the tumor site and secretion of cytokines characteristic of effector T helper cells (Th) subsets in plasma. Lastly, we observed the expression of several proteins involved in apoptosis, stress, and drug resistance in response to treatment with 5-FU in two microsatellite unstable (MSI) CRC cell lines, one from an AA and one from a CA patient, and a microsatellite stable (MSS) CA colon cancer cell line. Methods: We performed whole transcriptome sequencing in colon tumors, utilizing the NextSeq 500/550 High Output Kit v2.5 (Illumina). ELISA assays (RayBiotech) were used to examine the secretion of cytokines linked to Th subsets (Th1, Th2, Th17) and inflammation in plasma. Using IHC we evaluated the cell recruitment and activation of T and Natural Killer cells in colon tumors and by MetaCore we correlated gene expression to immune-oncology pathways. Western blots were used to evaluate the expression of cleaved caspase 3, phospho-JNK and RRM1 in the in-vitro models. Results: ELISAs of plasma from CA and AA patients revealed a differential Th cytokines production patterns between early stage (I, II) and late stage (III) disease. Our gene expression results indicate that the immune profiles of AA patients differ from CA in the expression of 36 key genes and cytokines related to cellular anti-tumor activity, including FOXP3, Granzyme B and IL-17A, suggestive of more favorable prognosis in the CA tumors. Lastly, the MSI AA cell line showed sensitivity to 5-FU in terms of protein expression when compared to the CA cell lines. Conclusions: Our gene expression findings demonstrated the differential expression of immunological pathways involved in immune-surveillance, cancer progression and antigen presentation in colon tumors from these two ethnicities. These results were in accordance with the systemic cytokines’ expression patterns observed in plasma and cell recruitment to the tumor sites. Importantly, our data indicates that treatment with 5-FU chemotherapy promotes apoptosis and stress in the MSI AA cell line but fails to produce the same effect in the CA cell lines at the same concentrations. Taken together, the differences in the immunological profiles in AA when compared to CA suggests a deficiency of the appropriate immune defense mechanisms in this population that may contribute to the cancer disparities among CRC patients. Citation Format: Jenny Paredes, Jone Garai, Ping Ji, Sayed Imtiaz, Marzia Spagnardi, Maria Munoz-Sagastibelza, Mubarak Akadri, Raavi Gupta, Mohamed Alshal, Maksim Agaronov, Henry Talus, Ellen Li, Jennie Williams, Jovanny Zabaleta, Laura Martello-Rooney. Gene expression and mutational load in colon tumors from African American patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 152.

Эффективность белков аллогенных гепатоцитов в коррекции иммунометаболических нарушений при остром ишемическом поражении печени

Objective. The aim of the study was to establish the effectiveness of the culture fluid of allogeneic hepatocytes (CFAH) and proteins isolated from them in correcting metabolic and immune disorders in acute ischemic liver damage. Material and methods. The study has been conducted on 105 healthy mature Wistar rats. Acute ischemic liver damage (AILD) was induced by cross clamping of the hepatoduodenal ligament for 20 minutes. Isolated allogeneic hepatocytes from newborn animals were used to prepare a culture fluid from which proteins were isolated. The culture fluid of allogeneic hepatocytes (CFAH) and their proteins obtained were administered with the start of modeling acute liver ischemia five times (with a 24-hour interval) intraperitoneally to rats with AILD at the rate of 5 mg/kg. Results. Acute liver ischemia causes the development of biochemical syndromes of the liver damage (cytolysis, intra- and extrahepatic cholestasis, toxic damage, insufficiency of synthetic processes) activates the processes of lipid peroxidation, disturbs intra-erythrocyte metabolism, and causes the development of oxidative stress and suppression of forming the adaptive and innate immunity. Introduction of CFAH, undivided CFAH proteins or CFAH proteins with molecular mass (MM) less than 130 kDa to animals with AILD normalizes or corrects the studied biochemical and immunological parameters. CFAH proteins with MM more than 130 kDa do not have such effects. Conclusion. During the analysis of CFAH or CFAH proteins corrective activity on the dynamics of biochemical markers of AILD, formation of humoral and cellular immunity, impaired functional and metabolic activity of peripheral blood neutrophils, intraerythrocyte metabolism, activation of free radical oxidation, the following sequence has been established (according to increasing the effectiveness): the lack of this activity in CFAH proteins with MM more than 130 kDa; the presence of normalizing and correcting activity of: CFAH - CFAH undivided proteins - CFAH proteins less than 130 kDa.

AKTIVITAS IMUNOMODULATOR FRAKSI ETIL ASETAT DAUN SOM JAWA (Talinum paniculatum (Jacq.) Gaertn) TERHADAP RESPON IMUN SPESIFIK

ABSTRACTEthyl acetate fraction of Som Java leaves (Talinum paniculatum (Jacq.) Gaertn) has been shown to boost innate immunity in the body (non-specific immunomodulatory activity). This study aims to determine the immunomodulatory activity of the specific response of the ethyl acetate fraction of Som Java leaves (Talinum paniculatum (Jacq.) Gaertn). Test specific immune response by using delayed type hypersensitivity test and total antibody titers test. Analysis of data obtained using SPSS version 16.0. Delayed type hypersensitivity test results showed that the ethyl acetate fraction Som Java leaves 50, 100 and 150 mg/kgbw proven to increase cellular immune response and activities comparable to the positive control. Total antibody titer test results showed that the fraction of ethyl acetate Som Java leaves three doses shown to increase the value of primary and secondary antibody titers. Based on the test results specific response can be concluded that the ethyl acetate fraction Som Java leaves have specific immunomodulatory activity.Keywords: Talinum paniculatum (Jacq.) Gaertn, immunomodulatory, delayed type hypersensitivity, total antibody titer test

Mechanical stress to Drosophila larvae stimulates a cellular immune response through the JAK/STAT signaling pathway

Acute inflammation can cause serious tissue damage and disease in physiologically-challenged organisms. The precise mechanisms leading to these detrimental effects remain to be determined. In this study, we utilize a reproducible means to induce cellular immune activity in Drosophila larvae in response to mechanical stress. That is, forceps squeeze-administered stress induces lamellocytes, a defensive hemocyte type that normally appears in response to wasp infestation of larvae. The posterior signaling center (PSC) is a cellular microenvironment in the larval hematopoietic lymph gland that is vital for lamellocyte induction upon parasitoid attack. However, we found the PSC was not required for mechanical stress-induced lamellocyte production. In addition, we observed that mechanical injury caused a systemic expression of Unpaired3. This cytokine is both necessary and sufficient to activate the cellular immune response to the imposed stress. These findings provide new insights into the communication between injured tissues and immune system induction, using stress-challenged Drosophila larvae as a tractable model system.

Heterologous vaccination targeting prostatic acid phosphatase (PAP) using DNA and Listeria vaccines elicits superior anti-tumor immunity dependent on CD4+ T cells elicited by DNA priming

ABSTRACTBackground. Sipuleucel T, an autologous cell-based vaccine targeting prostatic acid phosphatase (PAP), has demonstrated efficacy for the treatment of advanced prostate cancer. DNA vaccines encoding PAP and live attenuated Listeria vaccines have entered clinical trials for patients with prostate cancer, and have advantages in terms of eliciting predominantly Th1-biased immunity. In this study, we investigated whether the immunogenicity and anti-tumor efficacy of a DNA and Listeria vaccine, each encoding PAP, could be enhanced by using them in a heterologous prime/boost approach.Methods. Transgenic mice expressing HLA-A2.01 and HLA-DRB1*0101 were immunized alone or with a heterologous prime/boost strategy. Splenocytes were evaluated for MHC class I and II-restricted, PAP-specific immune responses by IFNγ ELISPOTs. Anti-tumor activity to a syngeneic, PAP-expressing tumor line was evaluated.Results. PAP-specific cellular immunity and anti-tumor activity were elicited in mice after immunization with DNA- or listeria-based vaccines. Greater CD4+ and CD8+ responses, and anti-tumor responses, were elicited when mice were immunized first with DNA and boosted with Listeria, but not when administered in the opposite order. This was found to be dependent on CD4+ T cells elicited with DNA priming, and was not due to inflammatory signals by Listeria itself or due to B cells serving as antigen-presenting cells for DNA during priming.Conclusions. Heterologous prime/boost vaccination using DNA priming with Listeria boosting may provide better anti-tumor immunity, similar to many reports evaluating DNA priming with vaccines targeting foreign microbial antigens. These findings have implications for the design of future clinical trials.

Dynamics of cytokine profile indexes in children with first diagnosed pulmonary tuberculosis in the course of antimycobacterial therapy

Antimycobacterial therapy is the main method of tuberculosis treatment. But some antimycobacterial medications have an unfavorable influence on the immune system and this fact significantly decreases efficiency of treatment and requires an additional pathogenetic immunocorrection.The aim of the work – to research dynamics of cytokine profile indexes in blood serum of children with first diagnosed pulmonary tuberculosis in the course of antimycobacterial therapy depending on specific process prevalence and to assess efficiency of antimycobacterial therapy after the basic course of treatment completion for further immunocorrecting therapy development.Materials and methods. Study of cytokine profile indexes was performed in 28 children with first diagnosed pulmonary tuberculosis from 1 to 16 years old (the average age was 9.2 ± 1.1 years). Depending on the specific process prevalence children with first diagnosed pulmonary tuberculosis were divided into two groups: the first group included 17 persons with a disseminated process and the second group included 11 persons with an isolated process. The comparison group included 30 healthy children. Comparison groups were age-matched and gender-matched. Cytokine profile indexes were studied by means of IL-2, IL-6, IL-4, IL-10 levels detection in blood serum through enzyme-linked immunosorbent assay using immunoenzymometric reader Sirio S and a set “Bender MedSystems GmbH” (Austria), (pg/ml). Dynamics of cytokine indexes was studied at the beginning of the antimycobacterial therapy intensive phase, on completion of the antimycobacterial therapy intensive phase (2 months after treatment) and on completion of the antimycobacterial therapy maintenance phase (6 months after treatment). Parents of all sick children signed patient’s written informed consent for participation in this study. Results of this work were processed by the modern methods of analysis with the help of a personal computer and the statistical package of the licensed software program Statistica® for Windows 6.0 (StatSoft Inc., № AXXR712 D833214FAN5).Results. A significantly high level of pro-inflammatory cytokine IL-2 characterized Тh1-type of cellular immune response high activity in children with first diagnosed pulmonary disseminated tuberculosisthroughout the entire course of antimycobacterial therapy. And significantly stably low levels of anti-inflammatory cytokines IL-4 and IL-10 indicated insufficiency of anti-inflammatory response throughout the entire course of antimycobacterial therapy. Calculation of cytokine indexes (and namely the IL-2/IL-10 ratio) has conformed that there was a disbalance between pro-inflammatory and anti-inflammatory cytokines towards pro-inflammatory cytokines with predominance of Тh1-type cellular immune response which lasted during the entire course of antimycobacterial therapy and tended to decline on its completion. Even though that in the course of antimycobacterial therapy in children with bacterioexcretion this process stopped, average duration of in-patient treatment was 9–10 months and that was 3 months longer than standard treatment of patients with first diagnosed pulmonary tuberculosis. The warning sign is also that among children with disseminated tuberculosis there were 3 cases (17.6 %) of multidrug-resistant tuberculosis in the course of treatment and in case with 1 child (5.9 %) lung destruction was persisted on the treatment completion.Conclusions. Children with first diagnosed pulmonary tuberculosis (regardless of the specific process prevalence) had a high activity of Th1-type cellular immune response against the background of an extremely decreased activity of Th2-type cellular immune response throughout the entire course of antimycobacterial therapy. This fact indicates insufficiency of anti-inflammatory response. At the same time all children had a pronounced disbalance between pro-inflammatory and anti-inflammatory cytokines towards pro-inflammatory ones on completion of the treatment basic course. These changes may contribute to the specific process progression as well as early recurrences of the disease.

Inorganic arsenic causes apoptosis cell death and immunotoxicity on European sea bass (Dicentrarchus labrax)

Inorganic arsenic (As) is one of the most toxic pollutants in the water. We have studied their effects on the marine teleost European sea bass (Dicentrarchus labrax) at 2 and 10 days of 5 μM of As2O3 (sub-lethal doses) waterborne exposure. Arsenic accumulates in liver and gill tissues. The expression profile of five genes (bax, blc2, casp3, casp8 and casp9) involved in apoptosis cell death confirmed apoptotic effects in liver, slight changes in gill and no effects in skin according with the histopathology findings. Total IgM level and peroxidase activities were increased at 2 and 10 days, respectively. The bactericidal activity was decreased at 2 days after As exposure. A general decrease of cellular immune activities with significant differences in the case of respiratory burst activity was observed after 2 and 10 days of exposure. This work describes for the first time the effects of As exposure on European sea bass.

Host Lipid Mediators in Leprosy: The Hypothesized Contributions to Pathogenesis.

The spectrum of clinical forms observed in leprosy and its pathogenesis are dictated by the host’s immune response against Mycobacterium leprae, the etiological agent of leprosy. Previous results, based on metabolomics studies, demonstrated a strong relationship between clinical manifestations of leprosy and alterations in the metabolism of ω3 and ω6 polyunsaturated fatty acids (PUFAs), and the diverse set of lipid mediators derived from PUFAs. PUFA-derived lipid mediators provide multiple functions during acute inflammation, and some lipid mediators are able to induce both pro- and anti-inflammatory responses as determined by the cell surface receptors being expressed, as well as the cell type expressing the receptors. However, little is known about how these compounds influence cellular immune activities during chronic granulomatous infectious diseases, such as leprosy. Current evidence suggests that specialized pro-resolving lipid mediators (SPMs) are involved in the down-modulation of the innate and adaptive immune response against M. leprae and that alteration in the homeostasis of pro-inflammatory lipid mediators versus SPMs is associated with dramatic shifts in the pathogenesis of leprosy. In this review, we discuss the possible consequences and present new hypotheses for the involvement of ω3 and ω6 PUFA metabolism in the pathogenesis of leprosy. A specific emphasis is placed on developing models of lipid mediator interactions with the innate and adaptive immune responses and the influence of these interactions on the outcome of leprosy.

Effects of dietary administration of fenugreek seeds on metabolic parameters and immune status of gilthead seabream (Sparus aurata L.)

Medical plants could be used as a prophylactic method in aquaculture because they are considered safe and so very promising alternatives to the use of chemicals. The aim of the present work was to examine the effects of dietary fenugreek (Trigonella foenum graecum) seeds administered for 8 weeks on the metabolic and immune status of gilthead seabream (Sparus aurata L.). Four experimental groups were designated: one receiving a basal diet (control) and three fed powdered fenugreek seeds incorporated in the fish feed at 1%, 5% and 10%. The results show that significant decreases in aspartate aminotransferase, creatine kinase, potassium and the albumin/globulin ratio were detected in the serum of fish fed 10% fenugreek compared with the values recorded in control fish. As regards the immune status, fish fed the 5% supplemented diet had higher haemolytic complement and peroxidase activities than the control fish whilst antiprotease activity was higher in fish fed the 1% fenugreek level respect to control fish and the fish fed the highest fenugreek supplementation rate. Interestingly, the results also revealed a significant enhancement of most of the cellular immune parameters studied, especially in fish fed the highest level of fenugreek (10%). However, the bacteriostatic activity of serum against fish pathogenic and non-pathogenic bacteria was non-affected to any significant extent in fish fed the supplemented diets. Overall, the results suggest that the high level of dietary fenugreek tested in this work (10%) did not negatively affect any of the metabolic parameters measured in serum but increased some of them. In addition, the inclusion of fenugreek seeds in the gilthead seabream diet at 5% or 10% improved the humoral and cellular immune activities, respectively. Further studies are needed to better understand the effects of this natural product, which may be suitable for use as a feed additive in fish aquaculture.

Phase II trial of ipilimumab in melanoma patients with preexisting humoural immune response to NY-ESO-1

BackgroundImmune checkpoint therapy has dramatically changed treatment options in patients with metastatic melanoma. However, a relevant part of patients still does not respond to treatment. Data regarding the prognostic or predictive significance of preexisting immune responses against tumour antigens are conflicting. Retrospective data suggested a higher clinical benefit of ipilimumab in melanoma patients with preexisting NY-ESO-1–specific immunity. Patients and methodsTwenty-five patients with previously untreated or treated metastatic melanoma and preexisting humoural immune response against NY-ESO-1 received ipilimumab at a dose of 10 mg/kg in week 1, 4, 7, 10 followed by 3-month maintenance treatment for a maximum of 48 weeks. Primary endpoint was the disease control rate (irCR, irPR or irSD) according to immune-related response criteria (irRC). Secondary endpoints included the disease control rate according to RECIST criteria, progression-free survival and overall survival (OS). Humoural and cellular immune responses against NY-ESO-1 were analysed from blood samples. ResultsDisease control rate according to irRC was 52%, irPR was observed in 36% of patients. Progression-free survival according to irRC was 7.8 months, according to RECIST criteria it was 2.9 months. Median OS was 22.7 months; the corresponding 1-year survival rate was 66.8%. Treatment-related grade 3 AEs occurred in 36% with no grade 4–5 AEs. No clear association was found between the presence of NY-ESO-1–specific cellular or humoural immune responses and clinical activity. ConclusionIpilimumab demonstrated clinically relevant activity within this biomarker-defined population. NY-ESO-1 positivity, as a surrogate for a preexisting immune response against tumour antigens, might help identifying patients with a superior outcome from immune checkpoint blockade.Clinical trial information: NCT01216696

Activity of the T- and B-system of the cell immunity of animals under conditions of oxidation stress and effects of the liposomal drug

The results of research on the influence of the elaborated complex immunotropic drug containing butafosfan, interferon, thistle and fat-soluble vitamins A, D3, E in the form of a liposomal emulsion on the activity of T- and B-cell chains of immunity in rats under the conditions of action on the body of oxidative stress are presented. It has been established that the introduction of 50% tetrachloromethane into the rats of the first and second experimental groups, with a dose of 0.25 ml per 100 g of body weight, causes oxidative stress in them which negatively affects the cellular immunity and functional activity of immunocompetent blood cells. Immunosuppressive effects of oxidative stress were manifested by a decrease in the blood of rats in the first and second experimental groups of the number of T- and B-lymphocytes and their regulatory subpopulations mainly on the 2nd and 5th day of the study. At the same time, in the blood of rats of the first experimental group in all research periods a decrease in the relative number of common, active and theophylline-resistant T-lymphocytes, as well as B-lymphocytes was observed with a noticeable increase in the number of their undifferentiated forms. At the same time, the obtained data suggest the positive effect of butafosfan, interferon, thistle and vitamins A, D3, E in the liposomal preparation on the relative amount of T- and B-lymphocytes and on the redistribution of avidity in the direction of strengthening the receptor field of plasma membranes immunocompetent cells. It was found that the normalization on the 2nd day of blood level in the second experimental group of common T-lymphocytes occurred due to the secondary forms of the blood and active T-lymphocytes by changes in the number of low-avid forms. In addition to the indicators characterizing the cellular immunity of rats, the components of the liposomal preparation showed regulatory influence on the humoral link of the immune response. In particular, on the 10th day of research in blood of rats of the second experimental group a tendency towards an increase in the relative number of B-lymphocytes and an increase in the number of cells with low and medium density of receptors was found, which, under the conditions of oxidative stress, indicates an increase in the body's ability to actively synthesize protective antibodies

Invitro effects of virgin microplastics on fish head-kidney leucocyte activities.

Microplastics are well-documented pollutants in the marine environment that result from production or fragmentation of larger plastic items. The knowledge about the direct effects of microplastics on immunity, including fish, is still very limited. We investigated the invitro effects of microplastics [polyvinylchloride (PVC) and polyethylene (PE)] on gilthead seabream (Sparus aurata) and European sea bass (Dicentrarchus labrax) head-kidney leucocytes (HKLs). After 1 and 24 h of exposure of HKLs with 0 (control), 1, 10 and 100 mg mL-1 MPs in a rotatory system, cell viability, innate immune parameters (phagocytic, respiratory burst and peroxidase activities) and the expression of genes related to inflammation (il1b), oxidative stress (nrf2, prdx3), metabolism of xenobiotics (cyp1a1, mta) and cell apoptosis (casp3) were studied. Microplastics failed to affect the cell viability of HKLs. In addition, they provoke very few significant effects on the main cellular innate immune activities, as decrease on phagocytosis or increase in the respiratory burst of HKLs with the highest dose of microplastics tested. Furthermore, microplastics failed to affect the expression of the selected genes on sea bass or seabream, except the nrf2 which was up-regulated in seabream HKLs incubated with the highest doses. Present results seem to suggest that continue exposure of fish to PVC or PE microplastics could impair fish immune parameters probably due to the oxidative stress produced in the fish leucocytes.

THE ADAPTIVE IMMUNE STATUS IN REPRESENTATIVES OF VARIOUS SOCIAL AND PROFESSIONAL GROUPS OF INHABITANTS OF THE EUROPEAN NORTH OF THE RUSSIAN FEDERATION

The analysis of the immune status with definition of cellular immunity (CD3+, CD4+, CD5+, CD8+, CD16+, CD95+, HLA-DR+) and fagotsitarny activity has been carried out in 356 men at the age of 20-40 years of the different social and professional groups (leading a nomadic, settled life in the tundra; working on a rotational basis in the North Sea (16 and 256 days); office employees of the Solombala pulp and paper mill (PPM) not occupied in harmful production; office workers of the megalopolis Moscow). It has been revealed that the most frequent defect of immune protection was a low level of active phagocytes and deficiency of maintenance of mature T-lymphocytes in peripheral blood among nomadic inhabitants of the Arctic and persons working short watch in the North Sea. It has been proved that under the influence of extreme social and professional or ecologo-climatic factors in men of 20-40 years increase of neutrophiles, sells-activators of B-lymphocytes (HLA-DR+) was registered that testifieed to tension of a humoral component of adaptive immune system. It has been stated that in the conditions of impact on a human body with a complex of various adverse factors of changing environment in all surveyed the same reaction of increase in levels of the cellular cytotoxicity (CD8+, CD16+) associated with deficiency of phagocytic protection developed that reduced spare capacities of regulation with risk of formation of T-lymphocytes functional insufficiency and development of secondary ecologically dependent immune imbalances.

Antidepressant efficacy of electroconvulsive therapy is associated with a reduction of the innate cellular immune activity in the cerebrospinal fluid in patients with depression

Objectives: A bidirectional link between the antidepressant effects of electroconvulsive therapy (ECT) and the modulation of the immune system has been proposed. To elucidate the interplay between antidepressant treatment and macrophage/microglia activation in humans, we performed a study on the effects of the antidepressant treatment by ECT on markers of macrophage/microglia activation in patients with depression.Methods: We measured six different markers (IL-6, neopterin, sCD14, sCD163 MIF and MCP1) of macrophage/microglia activation in the cerebrospinal fluid (CSF) and blood of 12 patients with a severe, treatment-resistant depressive episode before and after a course of ECT.Results: Some markers in the CSF of remitters were reduced after the ECT course and differed from non-remitters, but no differences were found before and after ECT independently from the antidepressant efficacy. CSF baseline levels of some markers could predict the reduction of depressive psychopathology during ECT. Higher CSF levels indicating increased macrophage/microglia activation at baseline predicted a better treatment response to ECT.Conclusions: Although the sample size was small, our data suggest that macrophages/microglia are involved in the pathophysiology of major depression and that antidepressant efficacy by ECT might be partly explained by the modulation of the innate immune system within the brain.