Lower Levels Of IL-6 Research Articles

High plasma IL-6 levels may enhance the adverse effects of mouse allergen exposure in urban schools on asthma morbidity in children

Few data on the relationships between environmental exposures, asthma morbidity, and systemic IL-6 inflammation exist. We sought to determine whether baseline plasma IL-6 level is associated with increased asthma morbidity in children exposed to mouse allergen in inner-city classrooms. Data from the longitudinal School Inner-City Asthma Studies of 215 children with asthma, aged 4 to 14 years and recruited from urban elementary schools, were analyzed. Given the unknown threshold of IL-6 risk levels and skewness of the distribution, the children were stratified into tertiles as follows: low baseline IL-6 level (<0.013 pg/mL), moderate baseline IL-6 level (0.013-0.302 pg/mL), and high baseline IL-6 level (>0.302 pg/mL). Relationships between plasma IL-6 level and body mass index (BMI) percentile, inflammatory markers, lung function, mouse allergen exposure, and asthma outcomes were assessed. Cross-sectional analysis demonstrated that increasing IL-6 level was associated with higher BMI percentile (P< .0001), C-reactive protein level (P= .0006), and blood neutrophil count (P= .0024). IL-6 was not associated with type 2 inflammatory markers, including blood eosinophil count, allergic sensitization, or fractional exhaled nitric oxide level. Longitudinal analysis showed that children with high IL-6 levels had a higher number of days with asthma symptoms than did those children with moderate (incidence rate ratio= 1.74 [95% CI= 1.10-2.77]; P= .0187) or low (incidence rate ratio=1.83 [95% CI= 1.21-2.77]; P= .0043) IL-6 levels. Children with high IL-6 levels who were exposed to increasing levels of mouse allergen exhibited lower ratios of FEV1 value to forced vital capacity than did children with moderate IL-6 levels (β= -0.0044 [95% CI= -0.0073 to -0.0015]; pairwise interaction P= .0028) or low IL-6 levels (β= -0.0042 [95% CI= - 0.0070 to -0.0013]; pairwise interaction P= .0039). Inner-city children with asthma and high plasma IL-6 levels are more likely to have an increased BMI, elevated C-reactive protein level, elevated blood neutrophil count, and greater asthma symptoms. High IL-6 level appears to increase susceptibility to the effects of classroom exposure to mouse allergen on lung function in urban children.

Immunomodulatory effect of vitamin D supplementation on Behçet’s disease patients: effect on nitric oxide and Th17/Treg cytokines production

Introduction In the last decade, an immuno-modulatory effect of vitamin D supplementation have emerged as a potential therapeutic approach for some inflammatory and autoimmune diseases. As previously reported, vitamin D deficiency was strongly linked to several diseases as Behçet’s disease (BD). BD is a chronic systemic inflammatory disorder with autoimmunity, genetic and environmental factors involvement. The aim of our current study is to set up a new therapeutic strategy in BD, combining conventional therapy and vitamin D supplementation. Materials and Methods Blood samples were collected from active and inactive BD patients and healthy controls (HC) to evaluate 25(OH) vitamin D levels using an electrochemiluminescence method. All deficient and insufficient vitamin D BD patients’ were supplemented with vitamin D3 (CHOLECALCIFEROL, 200 000 UI/1 ml). In this context, NO, IL-17A and IL-10 levels were evaluated in patients and HC in vivo and ex vivo using Griess and ELISA methods respectively. Results Before supplementation, we noted with interest that BD patients had vitamin D deficiency, associated with elevated in vivo and ex vivo NO and IL-17A levels compared to HC. Conversely, low IL-10 levels were observed in the same BD patients in comparison to HC. Interestingly, restored vitamin D status in supplemented BD patients was related to the decreased NO levels. In the same way, the IL-10/IL-17A ratio was improved. Conclusions Collectively, our data suggest that vitamin D supplementation in combination with conventional treatments has a beneficial effect and could constitute a good therapeutic candidate for alleviating inflammatory responses during Behçet disease.

Expression and Prognostic Value of Cytokines in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

To investigate the expression and prognostic value of cytokines in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Clinical data of 62 patients diagnosed with DLBCL in the First People's Hospital of Yunnan Province from June 2017 to November 2018 were collected. The differences in expression levels of 14 serum cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL-22, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, TNF-β] in patients with different survival outcomes, and the impact of the cytokines on 3-year progression-free survival (PFS) and 3-year overall survival (OS) of patients with DLBCL were analyzed retrospectively. Among the 14 cytokines, only the expression of IL-10 was significantly different in patients with different survival outcomes (P =0.007). According to the receiver operating characteristic (ROC) curve, the optimal cut-off value for IL-10 was 11.74 pg/ml. Serum IL-10 was positively correlated with infection markers procalcitonin (PCT) (r =0.321, P =0.029), C-reactive protein (CRP) (r =0.320, P =0.013) and tumor burden index lactate dehydrogenase (LDH) (r =0.439, P <0.001) in newly diagnosed DLBCL patients. The level of IL-10 in patients with pulmonary infection was significantly higher than that in patients without pulmonary infection (P =0.012). However, there was no statistically significant difference on the 3-year survival outcomes between patients with or without pulmonary infection. There was no significant difference in IL-10 level in patients with different Ann Arbor stages (P >0.05). Patients with high IL-10 level (IL-10>11.74 pg/ml) had significantly higher LDH level than those with low IL-10 level (IL-10≤11.74 pg/ml) (P <0.001). The 3-year PFS rate and 3-year OS rate of DLBCL patients with high IL-10 level were significantly lower than those of low IL-10 level group [(44.4±11.7)% vs (81.8±5.8)%, P <0.001; (61.6±11.5)% vs (93.2±3.8)%, P =0.001]. Serum IL-10 level in newly diagnosed DLBCL patients can reflect the inflammatory state of the body, which may be related to tumor load. Newly diagnosed DLBCL patients with serum IL-10>11.74 pg/ml have higher early mortality and worse prognosis.

Protective efficacy of Toxoplasma gondii GRA12 or GRA7 recombinant proteins encapsulated in PLGA nanoparticles against acute Toxoplasma gondii infection in mice.

Toxoplasma gondii is an apicomplexan parasite that affects the health of humans and livestock, and an effective vaccine is urgently required. Nanoparticles can modulate and improve cellular and humoral immune responses. In the current study, poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles were used as a delivery system for the T. gondii dense granule antigens GRA12 and GRA7. BALB/c mice were injected with the vaccines and protective efficacy was evaluated. Mice immunized with PLGA+GRA12 exhibited significantly higher IgG, and a noticeable predominance of IgG2a over IgG1 was also observed. There was a 1.5-fold higher level of lymphocyte proliferation in PLGA+GRA12-injected mice compared to Alum+GRA12-immunized mice. Higher levels of IFN-g and IL-10 and a lower level of IL-4 were detected, indicating that Th1 and Th2 immune responses were induced but the predominant response was Th1. There were no significant differences between Alum+GRA7-immunized and PLGA+GRA7-immunized groups. Immunization with these four vaccines resulted in significantly reduced parasite loads, but they were lowest in PLGA+GRA12-immunized mice. The survival times of mice immunized with PLGA+GRA12 were also significantly longer than those of mice in the other vaccinated groups. The current study indicated that T. gondii GRA12 recombinant protein encapsulated in PLGA nanoparticles is a promising vaccine against acute toxoplasmosis, but PLGA is almost useless for enhancing the immune response induced by T. gondii GRA7 recombinant protein.

TRIM32 reduced the recruitment of innate immune cells and the killing capacity of Listeria monocytogenes by inhibiting secretion of chemokines

Listeria monocytogenes (Lm) is a facultative, intracellular Gram-positive pathogenic bacterium that causes sepsis, a condition characterized by persistent excessive inflammation and organ dysfunction. However, the pathogenesis of Lm-induced sepsis is unknown. In this research, we discovered that TRIM32 is required for innate immune regulation during Lm infection. Trim32 deficiency remarkably reduced bacteremia and proinflammatory cytokine secretion in mice with severe Lm infection, preventing sepsis. Trim32−/− mice had a lower bacterial burden after Lm infection and survived significantly longer than wild-type (WT) mice, as well as lower serum levels of inflammatory cytokines TNF-α, IL-6, IL-18, IL-12p70, IFN-β, and IFN-γ at 1 day post infection (dpi) compared to WT mice. On the other hand, the chemokines CXCL1, CCL2, CCL7, and CCL5 were enhanced at 3 dpi in Trim32−/− mice than WT mice, reflecting increased recruitment of neutrophils and macrophages. Furthermore, Trim32−/− mice had higher levels of macrophage-associated iNOS to kill Lm. Collectively, our findings suggest that TRIM32 reduces innate immune cells recruitment and Lm killing capabilities via iNOS production.Graphical

Clinico-Epidemiological Laboratory Findings of COVID- 19 Positive Patients in a Hospital in Saudi Arabia.

Understanding COVID-19's onset and clinical effects requires knowing host immune responses. To investigate the presence of IgM, IgG, and cytokine levels (IL-2 and IL-6) in individuals with COVID-19 who have had their diagnosis confirmed by PCR. This cross-sectional research included 70 adult ICU patients from King Abdullah Hospital in Bisha, Saudi Arabia. Subjects gave two blood samples. After hospital release, only 21 patients provided the second sample. Each patient provided a sample upon admission. Quantitative ELISAs evaluated IL-2, IL-6, and SARS-CoV-2-specific IgM and IgG antibodies. All patients were critically ill and unvaccinated against COVID-19. 46 (65.7%) of the patients were male, and their age range was 33-98 years (with a mean age of 66.5); 24.3%) were 51-61 years old. IgG was positive in all patients, although IgM predominated in 57/70 (81.4%) (6-1200 IU/mL). Total data analysis yielded these results. IL-6 was calculated at 10-1900 ng/mL, whereas IL-2 was 4-280. Discharged hospital patients had a statistically significant increase in IgM and IgG (P = 0.01, 0.004) but a statistically insignificant decline in IL-6 and IL-2 (P = 0.761, 0.071). Low IgM levels increased hospital stays. The study found lengthier hospital stays with higher IgG levels. The identification of IgM and IgG antibodies, greater IL-6 levels, and lower IL-2 levels can help diagnose and monitor COVID-19 infection.

Casein fibres for wound healing.

The name casein is given to a family of phosphoproteins which is commonly found in milk. Until recently, this was a constituent of milk that was commonly discarded; however today, it is widely used in health supplements all over the world. In this work, a high loading (50 wt%) of casein is mixed with a solution of polycaprolactone (PCL) to produce bandage-like fibres with an average fibre diameter of 1.4 ± 0.5 µm, which would be used to cover wounds in a series of tests with diabetic rats. Mouse fibroblast cell viability tests show that the casein-loaded fibres had little cytotoxicity with over 90% observed viability. A 14-day in vivo trial involving three groups of rats, used as control (no treatment), pure PCL fibres and casein-loaded fibres, showed that the casein within the fibres contributed to a significantly more extensive healing process. Histological analysis showed increased development of granulation tissue and follicle regrowth for the casein-loaded fibres. Further analysis showed that casein-loaded fibres have significantly lower levels of TNF-α, TGF-β IL-1β, NF-κB and IL-6, contributing to superior healing. The results presented here show an economical and simple approach to advanced wound healing.

MiR-375 antagonist modified ferroferric oxide nanoparticles inhibited invasion and migration of ovarian cancer cells

This experiment assessed the effect of miR-375 antagonist (mA) modified ferroferric oxide nanoparticles (FONPs) on ovarian cancer cells. SKOV 3 cells were assigned into blank group (normal culture SKOV 3 cells), control group (intervention with FONPs), and intervention group (mA-FONPs), followed by analysis of cell biological behaviors and expressions of Bax, Bcl-2, Caspase-3, E-cadherin, N-cadherin, Vimentin, TL-6, JAK2, and STAT3. The nanoparticles were spherical with excellent dispersion and about 77 nm. Compared with the other two groups, the intervention group showed decreased cell vitality, increased apoptosis (P &lt;0.05). Cell number (44.63+2.37)% and migration quantity (89.75+4.01)% decreased significantly after intervention (P &lt;0.05) along with higher levels of E cadherin, Bax, Caspase 3 activity and lower levels of Bcl-2, N-cadherin, Vimentin, IL-6, JAK2 and STAT3 (P &lt;0.05). miR-375 targeted and inhibited the activity of JAK2/STAT3 pathway, reducing levels of IL-6, p-JAK2, and p-STAT3, up-regulating the expression of Bax and Caspase-3, reducing levels of N-cadherin and Vimentin, and finally regulating cell apoptosis and inhibiting cell migration and invasion.

P-236 IL-6 levels in follicular-fluid and day5/6 spent culture drops indicate its role as a biomarker of oocyte maturation and an embryokine influencing embryo developmental competence

Abstract Study question To elucidate the role of IL-6 in folliculogenesis and embryo development during human in-vitro culture Summary answer High IL-6 levels in follicular-fluid positively correlate with oocyte maturity status whereas higher IL-6 secretome in day5/day6 spent culture media inversely correlates with blastocyst/ICM grades What is known already Although some studies have attempted to explore the correlation of FF IL-6 with fertilization and embryo development rates; the results have been inconclusive. Similarly, studies comparing FF IL-6 levels with endometrial receptivity and pregnancy outcomes have been ambiguous and contradictory. Recent research has reported improvement in bovine blastocyst ICM grades in culture media supplemented with IL-6. No study has yet evaluated the role of IL-6 as a biomarker of oocyte maturity nor investigated IL-6 as an embryokine that could regulate embryo developmental competence in humans. We have employed the FF metabolomic and Secretomic approach for IL-6 in human IVF cycles. Study design, size, duration Prospective study in women (25-35 years) undergoing IVF cycles (n = 256) for unexplained/tubal-factor infertility from 2018-2020. Only those women whose FF and day5/6 spent culture media sample could be obtained, were included. Women with endometriosis, PID, Genital Kochs were excluded. IL-6 levels were measured by diagnostic kit in spent micro-drops and FF (pooled per patient per cycle). Cycles were divided into Low and High IL-6 groups (FF: ≤ 47.5 and &amp;gt;47.5pg/ml; Spent Medium: &amp;lt;0.5 and ≥0.5pg/ml). Participants/materials, setting, methods Antagonist cycles involving COH with r-FSH and ICSI for all. Noted oocyte Nuclear maturity (GV/MI/MII). Oocyte Cytoplasmic maturity graded as Top and non-Top, based on presence of granulation, refractile bodies, sER, visco-elasticity. Post ICSI, oocytes cultured individually in 50µl single-step media micro-drops till day3 and shifted to fresh 50µl micro-drops for extended culture till day5/6. Blastocyst gradation was done using Gardner’s classification for expansion, ICM and trophectodermal cells. Statistical analysis done using graph-pad prism VI Main results and the role of chance High FF/IL-6 group (n = 103) had significantly higher proportion of MII (92.08 vs. 76.33%; p &amp;lt; 0.001) and top-quality (88.10 vs. 70.0%; p &amp;lt; 0.001) oocytes and fertilization rates (89.45 vs. 77.30%; p = 0.009) compared to Low FF/IL-6 group (n = 153) although total number of days of stimulation/gonadotropin dose, mean oocytes retrieved did not differ significantly between the two groups. Cleavage (84.64 vs. 75.92%; p = 0.061) and blastocyst formation (53.86 vs. 42.37%; p = 0.053) rate, although higher, did not differ significantly between the two FF/IL-6 groups. FF/IL-6 level correlated strongly with overall oocyte maturity status (Pearson r = 0.61, 95% CI 0.52-0.8). Threshold FF/IL-6 level for obtaining top-quality MII oocytes was &amp;gt;39.2pg/ml (ROCAUC = 86%, Sensitivity = 78%, Specificity = 83%). In D5/6 spent culture drops, likelihood of top-quality blastocyst formation (expansion grade ≥3 and ICM/TE grades AA/AB/BA) increased by 41% (odds ratio: 0.44, 95%CI: 0.4-0.5; χ2 p &amp;lt; 0.0001) if IL-6 concentration was &amp;lt;0.5 pg/ml. Lower culture-drop IL-6 levels correlated strongly with top ICM grades (Pearson r = −0.66, 95% CI 0.6-0.7). Highest IL-6 levels were found in spent culture-drops containing grade-C blastocysts whether on day5 or day6. IL-6 levels were comparatively higher in day6 than in day5 micro-drops, correlating with higher percentage of top-quality blastocysts on day5 than on day6. Threshold micro-drop IL-6 level for top-grade blastocyst &amp;lt;0.42 pg/ml. Limitations, reasons for caution We estimated IL-6 levels in pooled FF (per patient, per cycle). Although cumbersome &amp; time-consuming, it would be worthwhile to evaluate individual FF (per follicle, per patient, per cycle). Also, measuring IL-6 in spent media involving group embryo culture, may facilitate study of the probable paracrine effects of this ‘embryokine’. Wider implications of the findings IL-6 is a pleiotropic cytokine and its role/s in folliculogenesis, embryo development and endometrial receptivity is not yet clearly etched out. This study attempts to elucidate the functions of IL-6 in a systematic manner by deriving threshold values for obtaining top quality oocytes and blastocysts in human in-vitro culture conditions. Trial registration number NOT APPLICABLE

Role of gut microbiota in perioperative neurocognitive disorders after cardiopulmonary bypass surgery in rats with humanized gut flora

To investigate whether gut microbiota disturbance after cardiopulmonary bypass (CPB) contributes to the development of perioperative neurocognitive disorders (PND). Fecal samples were collected from healthy individuals and patients with PND after CPB to prepare suspensions of fecal bacteria, which were transplanted into the colorectum of two groups of pseudo-germ-free adult male SD rats (group NP and group P, respectively), with the rats without transplantation as the control group (n=10). The feces of the rats were collected for macrogenomic sequencing analysis, and serum levels of IL-1β, IL-6 and TNF-α were measured with ELISA. The expression levels of GFAP and p-Tau protein in the hippocampus of the rats were detected using Western blotting, and the cognitive function changes of the rats were assessed with Morris water maze test. In all the 3 groups, macrogenomic sequencing analysis showed clustering and clear partitions of the gut microbiota after the transplantation. The relative abundances of Klebsiella in the control group (P < 0.005), Akkermansia in group P (P < 0.005) and Bacteroides in group NP (P < 0.005) were significantly increased after the transplantation. Compared with those in the control group, the rats in group NP and group P showed significantly decreased serum levels of IL-1β, IL-6 and TNF-α and lowered expression levels of GFAP and p-Tau proteins (all P < 0.05). Escape platform crossings and swimming duration in the interest quadrant increased significantly in group NP (P < 0.05), but the increase was not statistically significant in group N. Compared with those in group P, the rats in group NP had significantly lower serum levels of IL-1β, IL-6 and TNF-α and protein expressions of GFAP and p-Tau (all P < 0.05) with better performance in water maze test (P < 0.05). In patients receiving CPB, disturbances in gut mirobiota contributes to the development of PND possibly in relation with inflammatory response.

Life Stressors and Immunological Aging: Protective Effects of Cognitive Reappraisal

Stress may accelerate the aging of the immune system in ways that increase morbidity and mortality. However, effective emotion regulation may attenuate these stress-immune links. The current study tested whether cognitive reappraisal, which involves reframing an emotional event to change its impact, moderates the associations between life event stressors on markers of immunological aging in a longitudinal study of older adults. Participants (N=139, 58% female, Mage=78 years) reported their frequency of life event stressors, use of cognitive reappraisal, and provided blood every six months up to 10 times. Markers of immunological aging included percentages of late-differentiated T and natural kill (NK) cells and levels of systemic inflammation (interleukin-6 [IL-6], and C-reactive protein [CRP]). Multilevel models that adjusted for demographic and health covariates tested between- and within-person effects of life event stressors on immunological aging, moderated by reappraisal. The effects of life stressor frequency on late-differentiated NK cells between people and on IL-6 within people depended on reappraisal. On average, people who experienced more stressors but reported more use of reappraisal had lower percentages of late-differentiated NK cells. In addition, at times when people reported more stressors than their average but also used more reappraisal, they had lower levels of IL-6. Reappraisal did not moderate the associations between life stressors on T cells nor CRP. Emotion regulation and specifically cognitive reappraisal may play a protective role in attenuating the effects of life event stressors on aspects of innate immunological aging in older adults.

Effect of dihydroquercetin on the toxic properties of nickel nanoparticles

Dihydroquercetin (3,5,7,3',4'-pentahydroxy-flavanone) is known for its powerful antioxidant, organ-protective, and antiinflammatory activities that can be applied to heavy-metal intoxication. The present research objective was to evaluate the possible protective potential of dietary dihydroquercetin in a rat model of subacute (92 days) intoxication with nickel nanoparticles.&#x0D; The experiment involved five groups of twelve male Wistar rats in each. Group 1 served as control. Other groups received nickel nanoparticles as part of their diet. Groups 2 and 4 received nickel nanoparticles with an average diameter of 53.7 nm (NiNP1), while groups 3 and 5 were fed with nanoparticles with an average diameter of 70.9 nm (NiNP2). The dose was calculated as 10 mg/kg b.w. Groups 4 and 5 also received 23 mg/kg b.w. of water-soluble stabilized dihydroquercetin with drinking water. &#x0D; After the dihydroquercetin treatment, the group that consumed 53.7 nm nickel nanoparticles demonstrated lower blood serum glucose, triglycerides, low-density lipoprotein cholesterol, and creatinine. Dihydroquercetin prevented the increase in total protein and albumin fraction associated with nickel nanoparticles intake. The experimental rats also demonstrated lower levels of pro-inflammatory cytokines IL-1β, IL-4, IL-6, and IL-17A, as well as a lower relative spleen weight after the treatment. In the group exposed to 53.7 nm nickel nanoparticles, the dihydroquercetin treatment increased the ratio of cytokines IL-10/IL-17A and decreased the level of circulating FABP2 protein, which is a biomarker of increased intestinal barrier permeability. In the group that received 70.9 nm nickel nanoparticles, the dihydroquercetin treatment inhibited the expression of the fibrogenic Timp3 gene in the liver. In the group that received 53.7 nm nickel nanoparticles, dihydroquercetin partially improved the violated morphology indexes in liver and kidney tissue. However, dihydroquercetin restored neither the content of reduced glutathione in the liver nor the indicators of selenium safety, which were suppressed under the effect of nickel nanoparticles. Moreover, the treatment failed to restore the low locomotor activity in the elevated plus maze test.&#x0D; Dihydroquercetin treatment showed some signs of detoxication and anti-inflammation in rats subjected to nickel nanoparticles. However, additional preclinical studies are necessary to substantiate its prophylactic potential in cases of exposure to nanoparticles of nickel and other heavy metals.

Efficacy of an Immunotherapy Combining Immunogenic Chimeric Protein Plus Adjuvant and Amphotericin B against Murine Visceral Leishmaniasis.

Visceral leishmaniasis (VL) in the Americas is a chronic systemic disease caused by infection with Leishmania infantum parasites. The toxicity of antileishmanial drugs, long treatment course and limited efficacy are significant concerns that hamper adequate treatment against the disease. Studies have shown the promise of an immunotherapeutics approach, combining antileishmanial drugs to reduce the parasitism and vaccine immunogens to activate the host immune system. In the current study, we developed an immunotherapy using a recombinant T cell epitope-based chimeric protein, ChimT, previously shown to be protective against Leishmania infantum, with the adjuvant monophosphoryl lipid A (MPLA) and amphotericin B (AmpB) as the antileishmanial drug. BALB/c mice were infected with L. infantum stationary promastigotes and later they received saline or were treated with AmpB, MPLA, ChimT/Amp, ChimT/MPLA or ChimT/MPLA/AmpB. The combination of ChimT/MPLA/AmpB significantly reduced the parasite load in mouse organs (p < 0.05) and induced a Th1-type immune response, which was characterized by higher ratios of anti-ChimT and anti-parasite IgG2a:IgG1 antibodies, increased IFN-γ mRNA and IFN-γ and IL-12 cytokines and accompanied by lower levels of IL-4 and IL-10 cytokines, when compared to other treatments and controls (all p < 0.05). Organ toxicity was also lower with the ChimT/MPLA/AmpB immunotherapy, suggesting that the inclusion of the vaccine and adjuvant ameliorated the toxicity of AmpB to some degree. In addition, the ChimT vaccine alone stimulated in vitro murine macrophages to significantly kill three different internalized species of Leishmania parasites and to produce Th1-type cytokines into the culture supernatants. To conclude, our data suggest that the combination of ChimT/MPLA/AmpB could be considered for further studies as an immunotherapy for L. infantum infection.

Identification of cytokines associated with response and cytokine release syndrome: Analysis of MagnetisMM-3 cohort A.

8044 Background: MagnetisMM-3 (NCT04649359) is a phase 2 study of elranatamab monotherapy in patients with multiple myeloma refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Promising efficacy and safety have been observed in patients who were naïve to B-cell maturation antigen (BCMA)-directed therapy (Cohort A) in MagnetisMM-3 (Bahlis et al., ASH 2022). Methods: In MagnetisMM-3, patients received subcutaneous elranatamab in 28-day cycles with step-up doses of 12 mg on C1D1 and 32 mg on C1D4 followed by 76 mg QW beginning C1D8. Serum samples were collected on C1D1 prior to first priming dose, and on C1D2, pre-dose C1D4, C1D5, pre-dose C1D8, C1D15, and C1D22. Levels of 45 peripheral cytokines were analyzed by proximity extension assay and a longitudinal mixed effects model was applied to each cytokine separately. Cytokines with a significant 2-fold differential expression (responders [defined as patients with best overall response of very good partial response or better] vs non-responders [defined as patients with best overall response of partial response or worse]; cytokine release syndrome [CRS] vs no CRS) at any timepoint are reported. Clinical data cutoff was in Oct 2022 with median follow up of 10.4 months. Results: Baseline levels of IL-6 (2.6-fold), IL-17C (2.0-fold), and MIP-1α (2.1-fold) were lower in patients who achieved a response. After the first priming dose, 13 cytokines in the panel, including CCL8, IFN-γ, IL-2, and IL-27, were differentially expressed in responders vs non-responders. At baseline, no cytokines were found to predict CRS. After the first priming dose, 18 cytokines in the panel, including CCL8, IFN-γ, IL-10, IL-2, IL-27, IL-6, and IL-17A, were differentially expressed in patients with CRS vs no CRS. The maximal differential expression for 17/18 cytokines occurred at C1D2, ~24 hours post the first priming dose. Conclusions: Lower baseline levels of IL-6, IL-17C, and MIP-1α correlated with a response of VGPR or better in BCMA-naïve patients from MagnetisMM-3, suggesting that lower levels of these cytokines might reflect a favorable immune environment. Many cytokines were differentially expressed at higher levels in patients who experienced CRS vs those who did not; the most prominent cytokines included CCL-8, IFN-γ, and IL-10. The timing of induction of CCL-8, IFN-γ, and IL-10 occurred by C1D2 suggesting a potential contribution of these cytokines in driving CRS. Clinical trial information: NCT04649359 .

Immunological signature of patients with thymic epithelial tumors and Good syndrome: Correlation with clinical outcome.

e20648 Background: Thymic epithelial tumors (TETs) are extremely rare and heterogenous neoplasms, associated with immune dysregulation. Recognized prognostic factors are TNM stage and the Masaoka-Koga classification. To the best of our knowledge, no study has been conducted to investigate the correlation between immunophenotype, level of cytokines, chemochines and clinical outcome in TETs patients. The aim of this study was to evaluate the correlation of immunological signature and long-term outcome in patients with TETs and Good Syndrome (GS). Methods: From May 2019 to October 2022, consecutive patients with TETs and GS, referred to the Rare Tumors Coordinating Center of Campania Region (CRCTR) of Federico II of Naples, were enrolled. The immunophenotype of monocytes, neutrophils, eosinophils, CD4+ T cells, CD8 + T cells, B-cells, NK cells and NKT-cells, T regulatory cells, and the evaluation of serum levels of cytokines, chemokines and growth factors were assessed using the 8-color immunophenotyping kit, Treg detection kit and pre-formed Kits by Bioplex multiplex, respectively. D’Agostino-Pearson normality test was used to evaluate whether the continuous data were normally distributed, and a two-tailed t-test for independent samples was used. Overall survival (OS) analysis was performed generating Kaplan-Meier curves and Cox Univariate models for the considered categorical stratifications. p-values &lt; 0.05 were considered statistically significant. Results: A total of 24 consecutive TETs patients were included in the study: 13 (54.17%) patients were male and 11 (48.83%) were female, with a median age of 54.96 ± 9.6 years. Tumor histology included 20 thymoma, and 4 thymic carcinoma. Autoimmune diseases were found in 13 patients all of whom had thymoma. At the time of this analysis, 5 (20.83%) patients had no evidence of disease (NED) by imaging and were in follow-up, 17 (70.83%) patients were still alive. The analysis of leucocytes did not show statistically significant association with clinical outcome of TETs patients. On the contrary, a statistically significant correlation between serum concentration of IL-6 and OS was found with lower levels of IL-6 associated with poorer prognosis (HR: 9.654; p = 0.016). In addition, we found a statistically significant reduction of IL-2 (p = 0.04), IL-15 (p = 0.048), IL-5 (p = 0.03) and VEGF (p = 0.01) serum levels in patients with evidence of disease, as compared to NED patients. Conclusions: Overall, these findings suggest that measurement of IL-6 levels may be a useful parameter for identifying TETs patients with GS who have more aggressive diseases. Our preliminary data may be useful in the clinical management of this complex disease. Further studies are needed to better understand the pathophysiology and clinical implications of immunophenotype alterations in TETs patients.

A preliminary analysis of integrating thymosin α1 into concurrent chemoradiotherapy and consolidative immunotherapy.

e20569 Background: The study aimed to investigate the efficacy of integrating Thymosin into concurrent chemoradiotherapy (CCRT) and consolidative immunotherapy in unresectable locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Ninety-one stage IIIA-IIIC LA-NSCLC patients enrolled from Jan 1, 2020, to Oct 31, 2022 were analyzed retrospectively. All patients received CCRT (total irradiation dose of 60Gy and weekly concurrent docetaxel and cisplatin) and consolidative immunotherapy (Nivolumab/Tislelizumab). Thymosin α1 (1.6 mg) was administered once a week from the start of treatment till 2 months after CCRT or till the last prescription of consolidative immunotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints included the overall survival (OS) and toxicity. Results: There were 31 patients who received Thymosin α1 till the last prescription of consolidative immunotherapy, 40 patients received Thymosin α1 till 2 months after CCRT and 20 patients without the administration of Thymosin α1. The median follow-up time was 28.3 months (range 8.2~31.6 months). The median PFS was 26.1 months in Thymosin α1+consolidative immunotherapy group, 15.3 months in Thymosin α1+CCRT group and 12.6 months in control group (P = 0.116). The median OS was not reached in Thymosin α1+consolidative immunotherapy group, 26 months in Thymosin α1+CCRT group and 16.5 months in control group (P = 0.046). The median courses of consolidative immunotherapy were 8 Thymosin α1+consolidative immunotherapy group, 6 in Thymosin α1+CCRT group and 3 in control group (P = 0.060). There were higher ≥grade 3 acute lymphopenia (62.3%) and acute grade 2 pneumonitis (8.0%) in the control group. The long-term use of Thymosin α1 was also found to be related to the lower level of IL-6(P = 0.048), CD 16+NK cells and CD56+NK cells (P = 0.043). Conclusions: The integration of Thymosin α1 into CCRT and consolidative immunotherapy could yield synergistic effect in LA-NSCLC patients. The combination might contribute to prolonged use of consolidative immunotherapy and survival benefit.

Inflammatory cytokines in alcohol use disorder patients are lower in smokers and users of smokeless tobacco.

Smoking and alcohol use often cooccur, and the use of nicotine-containing products is particularly common among persons with alcohol use disorder (AUD). Recent evidence shows that chronic alcohol use leads to inflammation through increased gut permeability and dysregulated cytokine levels. While cigarette smoking also has detrimental health effects, nicotine is indicated to exert immune dampening effects in some settings. Preclinical evidence demonstrates that nicotine may dampen alcohol induced inflammation, but inflammatory responses after use of nicotine has not yet been studied in persons with AUD. The current study compared the level of circulating cytokines in non-tobacco users, smokers, users of Swedish snus and dual tobacco users among abstinent AUD inpatients. We collected blood samples and information about somatic and mental health, and tobacco habits from 111 patients in residential treatment for AUD and 69 healthy controls. Levels of interferon (IFN)-γ, interleukin (IL)-10, tumor necrosis factor (TNF)-α, IL-17a, IL-1β, IL-6, IL-8, IL-1 receptor antagonist (ra), and monocyte chemoattractant protein (MCP)-1 were examined using a multiplex assay. Patients with AUD had higher levels of seven cytokines compared to healthy controls. Among the AUD patients, nicotine users had lower levels of IL-10, TNF-α, IL-17a, IL-1β, IL-8, and MCP-1 (all p<0.05). Our findings may indicate that nicotine has anti-inflammatory effects in patients with AUD. Still nicotine use cannot be recommended as a viable therapeutic option to reduce alcohol-induced inflammation because it may cause other adverse effects. Future studies of cytokine patterns in relation to mental or somatic health conditions are warranted to carefully investigate the effect of nicotine, by monitoring the use of any tobacco or nicotine product.

Low body mass index is associated with diminished plasma cytokines and chemokines in both active and latent tuberculosis.

Low body mass index (BMI) is a major risk factor for tuberculosis (PTB). Low BMI can impair the immune system and thus might affect TB incidence. We examined the plasma levels of Type 1, Type 17, pro-inflammatory, Type 2 and regulatory cytokines and CC and CXC chemokines in PTB and latent TB (LTB) individuals with low BMI (LBMI) or normal BMI (NBMI). Our data show that PTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL-17A, IL-6, IL-12, IL-4 and IL-5 cytokines but significantly higher levels of IL-10, TGFβ and GM-CSF in LBMI compared to NBMI. Similarly, PTB is also associated with significantly lower levels of CCL2, CCL3, CCL11, CXCL1, CXCL9 and CXCL10 chemokines in LBMI compared to NBMI. Our data reveals that LTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL1β, IL-12, IL-13 cytokines but significantly higher levels of IL-10, TGFβ, IL-4 and IL-22 in LBMI compared to NBMI. Similarly, LTB is also associated with significantly lower levels of CCL2, CXCL1, CXCL9 and CXCL10 and significantly higher levels of CCL1, CCL3, and CCL4 in LBMI compared to NBMI. Thus, LBMI has a major impact on the cytokine and chemokine milieu of both PTB and LTB and might predispose to the increased risk of tuberculosis by this immunomodulatory effect.

Lupus nephritis: clinical characteristics, serological associations, pattern of pro- and anti-inflammatory markers

The present study aimed to investigate the prevalence, clinical, and laboratory characteristics of renal involvement in a large cohort of Ukrainian patients with systemic lupus erythematosus (SLE).&#x0D; Methods. A total of 380 patients with SLE were enrolled in this cross-sectional study, including 176 with lupus nephritis (LN) and 204 with non-renal SLE. Patients were reviewed for demographic details, clinical SLE manifestations, SLE Disease Activity Index 2000 (SLEDAI-2K), and SLICC/ACR Damage Index. Laboratory evaluations included complete blood count with an erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), anti-CRP antibodies, serum creatinine, complement C3 and C4 levels, urinalysis, 24-hour urine protein, specific autoantibodies, interleukin-6 (IL-6), IL-10.&#x0D; Results. There was a significantly higher frequency of malar rash, lymphadenopathy, splenomegaly, serositis, pulmonitis, fever, necrotizing vasculitis, and a history of arterial/venous thrombosis in patients with LN; while Raynaud’s phenomenon, Sjogren’s syndrome, peripheral nervous system manifestations occurred more often in patients with non-renal SLE. Patients with LN were found to have higher ESR levels and lower IL-10 levels. Either frequency of anti-dsDNA positivity and its titer were higher in the LN group with no differences regarding other autoantibodies. C3 and C4, CRP, hs-CRP, anti-CRP, and IL-6 levels showed no significant difference between the groups.&#x0D; Multivariate analysis demonstrated that LN was positively associated with pulmonitis (OR 5.34 (95% CI 1.88-15.10), p=0.002), arterial/venous thrombosis (OR 6.80 (95% CI 1.87-24.70), p=0.004), anti-dsDNA positivity (OR 6.22 (95% CI 1.89-20.50), p=0.003), higher SLEDAI-2K score (OR 1.15 (95% CI 1.08-1.23), p&lt;0.001) and negatively associated with Raynaud’s syndrome (OR 0.20 (95% CI 0.08-0.49), p&lt;0.001) and younger age at disease onset (OR 0.96 (95% CI 0.93-0.99), p=0.003).&#x0D; In the LN group, 27 patients (15.3%) had nephrotic syndrome. In multivariate logistic analysis, male sex (OR 5.21 (95% CI 1.77-15.30), p=0.003) and higher SLICC/ACR score (OR 2.12 (95% CI 1.45-3.09), p&lt;0.001) were associated with increased risk of nephrotic syndrome, whereas lymphadenopathy (OR 0.31 (95% CI 0.12-0.80), p=0.02) was associated with decreased risk of nephrotic syndrome development.&#x0D; Conclusions. Our cohort of Ukrainian LN patients showed different characteristics in demographic, clinical, and laboratory findings compared to patients with non-renal SLE. These features are mostly on par with LN patients of other nationalities around the world.

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma

Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8⁺ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.