Marker Of Cellular Immune Activation Research Articles

Prenatal and childhood air pollution exposure, cellular immune biomarkers, and brain connectivity in early adolescents

IntroductionAmbient air pollution is a neurotoxicant with hypothesized immune-related mechanisms. Adolescent brain structural and functional connectivity may be especially vulnerable to ambient pollution due to the refinement of large-scale brain networks during this period, which vary by sex and have important implications for cognitive, behavioral, and emotional functioning. In the current study we explored associations between air pollutants, immune markers, and structural and functional connectivity in early adolescence by leveraging cross-sectional sex-stratified data from the Adolescent Brain Cognitive Development℠ Study®. MethodsPollutant concentrations of fine particulate matter, nitrogen dioxide, and ozone were assigned to each child's primary residential address during the prenatal period and childhood (9-10 years-old) using an ensemble-based modeling approach. Data collected at 11-13 years-old included resting-state functional connectivity of the default mode, frontoparietal, and salience networks and limbic regions of interest, intracellular directional and isotropic diffusion of available white matter tracts, and markers of cellular immune activation. Using partial least squares correlation, a multivariate data-driven method that identifies important variables within latent dimensions, we investigated associations between 1) pollutants and structural and functional connectivity, 2) pollutants and immune markers, and 3) immune markers and structural and functional connectivity, in each sex separately. ResultsAir pollution exposure was related to white matter intracellular directional and isotropic diffusion at ages 11–13 years, but the direction of associations varied by sex. There were no associations between pollutants and resting-state functional connectivity at ages 11–13 years. Childhood exposure to nitrogen dioxide was negatively correlated with white blood cell count in males. Immune biomarkers were positively correlated with white matter intracellular directional diffusion in females and both white matter intracellular directional and isotropic diffusion in males. Lastly, there was a reliable negative correlation between lymphocyte-to-monocyte ratio and default mode network resting-state functional connectivity in females, as well as a compromised immune marker profile associated with lower resting-state functional connectivity between the salience network and the left hippocampus in males. In post-hoc exploratory analyses, we found that the PLSC-identified white matter tracts and resting-state networks related to processing speed and cognitive control performance from the NIH Toolbox. ConclusionsWe identified novel links between childhood nitrogen dioxide and cellular immune activation in males, and brain network connectivity and immune markers in both sexes. Future research should explore the potentially mediating role of immune activity in how pollutants affect neurological outcomes as well as the potential consequences of immune-related patterns of brain connectivity in service of improved brain health for all.

Investigation of neopterin levels in children with hashimoto thyroiditis

ABSTRACT Objective: Hashimoto Thyroiditis is an autoimmune disease caused by genetic and environmental factors and is known as the most common cause of hypothyroidism in childhood. Neopterin has been measured in many autoimmune disorders and has been identified as a marker of cellular immune activation. The aim of this study was to investigate the autoimmune association of neopterin in patients with Hashimoto's Thyroiditis aged 5-18 years. Material and Method: Neopterin levels were measured in 80 individuals, 40 of whom were followed up with the diagnosis of Hashimoto Thyroiditis and 40 of whom were not diagnosed with Hashimoto Thyroiditis. Results: While the mean value of neopterin levels in the control group participating in this study was 86.4170 ± 3.59284, the mean value in the patient group was 101.32 ± 9.75378. When we look at the participant age data, it is seen that the patients and controls are compatible with each other (p>0.05). In addition, it is seen that there is a significant positive correlation p

Opioids exacerbate inflammation in people with well-controlled HIV.

People with HIV (PWH) are known to have underlying inflammation and immune activation despite virologic control. Substance use including opioid dependence is common in this population and is associated with increased morbidity and reduced lifespan. The primary objective of the present study termed opioid immunity study (OPIS), was to investigate the impact of chronic opioids in PWH. The study recruited people with and without HIV who had opioid use disorder (OUD). Study participants (n=221) were categorized into four groups: HIV+OP+, n=34; HIV-OP+, n=66; HIV+OP-, n=55 and HIV-OP-, n=62 as controls. PWH were virally suppressed on ART and those with OUD were followed in a syringe exchange program with confirmation of OP use by urine drug screening. A composite cytokine score was developed for 20 plasma cytokines that are linked to inflammation. Cellular markers of immune activation (IA), exhaustion, and senescence were determined in CD4 and CD8 T cells. Regression models were constructed to examine the relationships of HIV status and opioid use, controlling for other confounding factors. HIV+OP+ participants exhibited highest inflammatory cytokines and cellular IA, followed by HIV-OP+ for inflammation and HIV+OP- for IA. Inflammation was found to be driven more by opioid use than HIV positivity while IA was driven more by HIV than opioid use. In people with OUD, expression of CD38 on CD28-CD57+ senescent-like T cells was elevated and correlated positively with inflammation. Given the association of inflammation with a multitude of adverse health outcomes, our findings merit further investigations to understand the mechanistic pathways involved.

The potential role of neopterin in Covid-19: a new perspective.

Neopterin (NPT) is a member of pteridines group, synthesized by macrophages when stimulated by interferon gamma (INF-γ). NPT is regarded as a macrophage stimulation indicator, marker of cellular immune activation and T helper 1 (Th1) type 1 immune response. Here, we aimed to provide a view point on the NPT features and role in Covid-19. Serum NPT level is regarded as an independent prognostic factor for Covid-19 severity, with levels starting to increase from the 3rd day of SARS-CoV-2 infection, being associated with severe dyspnea, longer hospitalization period and complications. Also, early raise of NPT reflects monocytes/macrophages activation before antibody immune response, despite the NPT level may also remain high in Covid-19 patients or at the end of incubation period before the onset of clinical symptoms. On the other hand, NPT attenuates the activity of macrophage foam cells and is linked to endothelial inflammation through inhibition of adhesion molecules and monocytes migration. However, NPT also exerts anti-inflammatory and antioxidant effects by suppressing NF-κB signaling and NLRP3 inflammasomes. NPT can be viewed as a protective compensatory mechanism to counterpoise hyper-inflammation, oxidative stress, and associated organ damage.

Effect of high intake of cod or salmon on serum total neopterin concentration: a randomised clinical trial

PurposePrimarily, to investigate the effect of high intake of cod (lean fish) or salmon (fatty fish) on serum concentration of total neopterin, a marker of cellular immune activation that is associated with cardiovascular disease. Second, to investigate effects of high cod/salmon intake on antioxidant vitamins and elements essential for activity of antioxidant enzymes.MethodsIn this randomised clinical trial, 63 participants with overweight/obesity consumed 750 g/week of either Atlantic cod (N = 22) or Atlantic salmon (N = 22) or were instructed to continue their normal eating habits but avoid fish intake (Control group, N = 19) for 8 weeks. Food intake was recorded, and fasting serum were collected at baseline and endpoint.ResultsSerum total neopterin concentration was reduced in the Cod group (median change − 2.65 (25th, 75th percentiles − 3.68, − 0.45) nmol/l, P = 0.018) but not in the Salmon group (median change 0.00 (25th, 75th percentiles − 4.15, 3.05) nmol/l, P = 0.59) when compared with the Control group after 8 weeks. The estimated daily intake of selenium, iron, magnesium and zinc were similar between all groups. Increased serum concentration of selenium was observed only after cod intake when compared to the Control group (P = 0.017). Changes in serum concentrations of copper, iron, magnesium, all-trans retinol, α-tocopherol and γ-tocopherol were similar between the groups.ConclusionA high intake of cod, but not of salmon, lowered serum total neopterin concentration when compared to the Control group.Clinical trial registrationThis trial was registered at clinicaltrials.gov as NCT02350595

Neutrophil-to-lymphocyte ratio, past, present and future perspectives

In the review we analyzed short history of the establishment of a novel hematological parameter for systemic inflammation and stress coined as a neutrophil to lymphocyte ratio (NLR). Today NLR is widely used across almost all medical disciplines as a reliable and easy available marker of immune response to various infectious and non-infectious stimuli. We analyzed the immunological and biological aspects of dynamic changes of neutrophil granulocytes and lymphocytes in circulating blood during endocrine stress, dysbalance of autonomic nervous system and systemic inflammation. NLR reflects online dynamic relationship between innate (neutrophils) and adaptive cellular immune response (lymphocytes) during illness and various pathological states. NLR is influenced by many conditions including age, rice, medication, chronic disease like coronary heart disease, stroke, diabetes, obesity, psychiatric diagnosis, cancer of solid organs, anemia and stress. A normal range of NLR is between 1-2, the values higher than 3.0 and below 0.7 in adults are pathological. NLR in a grey zone between 2.3-3.0 may serve as early warning of pathological state or process such like cancer, atherosclerosis, infection, inflammation, psychiatric disorders and stress. NLR is used as a reliable and cheap marker of ongoing cancer-related inflammation and a valid indicator of prognosis of solid tumors. Majority of meta-analyses have explored the prognostic value of NLR in various solid tumors and have found out the cut-off value of NLR above 3.0 (IQR 2.5-5.0). We summarized its privilege in oncology: NLR may be used for stratification of cancer, correlates with the tumor size, stage of tumors, metastatic potential and lymphatic invasion. NLR has independent prognostic role regarding overall, cancer free and cancer-specific survival. It is useful for monitoring oncological therapy, including biological and immune check point inhibitors treatment. NLR is a very sensitive indicator of infection, inflammation and sepsis, validated in numerous studies. Clinical research confirmed the sensitivity of NLR for diagnosis/stratification of systemic infection, sepsis, bacteremia as well as its robust predictive and prognostic value. NLR should be investigated daily, and follow-up its absolute values and dynamic course in acute disease or critical illness. The severity of critical illness, the level of stress and serious inflammation is expressed by dramatic increasing of NLR values above 11 ≥ 17, or even higher than 30. Improving the clinical course of sepsis, critical illness, lower risk of mortality are associated with decline of NLR values below 7. NLR is helpful in differentiating more severe disease versus milder one. NLR is cheap, simple, fast responding and easy available parameter of stress and inflammation with high sensitivity and low specificity, it should be used routinely in emergency departments, ICUs, in acute medicine including surgery, orthopedics, traumatology, cardiology, neurology, psychiatry and even oncology. Dynamic changes of NLR precede the clinical state for several hours and may warn clinicians about the ongoing pathological process early. NLR is a novel perspective marker of cellular immune activation, a valid index of stress and systemic inflammation, which open a new dimension for clinical medicine, for better understanding of the biology of inflammation, coupling and antagonism between innate and adaptive immunity and its clinical consequences for health and disease (Tab. 8, Fig. 3, Ref. 151). Keywords: neutrophil-to-lymphocyte ratio, systemic inflammation, immune-inflammatory response, endocrinne stress.

Soluble IL-2R\u03b1 correlates with imbalances of Th1/Th2 and Tc1/Tc2 cells in patients with acute brucellosis

BackgroundPrevious studies showed that soluble IL-2Rα is an important marker of cellular immune activation and might be a marker of treatment efficacy for children with brucellosis. However, data regarding adult patients with brucellosis were unknown. The aim of study was to explore the potential role of serum sIL-2Rα evaluating treatment responses in adult patients with brucellosis, and T cell immune status was also examined.MethodsDuring January 2016–April 2017, 30 patients with acute brucellosis from the Third People’s Hospital of Linfen in Shanxi Province and Beijing Di Tan Hospital, and 28 healthy controls were included in this study. Peripheral blood samples were collected before and after six weeks of antibiotic treatment. Serum sIL-2Rα levels were measured by enzyme-linked immunosorbent assay, and the percentage of Th1, Th2, Tc1, Tc2, and Tregs was detected by flow cytometry after intracellular staining for cytokines (interferon-γ and interleukin-4) and Foxp3 in T lymphocytes from peripheral blood. The obtained data were analyzed with Wilcoxon ranked sum tests for paired values, Mann-Whitney U-tests for comparisons between patients and healthy controls, and Spearman rank tests for correlation analyses.ResultsSerum sIL-2Rα levels were significantly higher in patients than in controls (P = 0.001). A significant decline was observed in patients after the cessation of treatment (P < 0.001) and return to normal (P > 0.05). Th1, Tc1, Th2, and Tc2 cell frequencies were higher in patients than in healthy subjects (P < 0.05), while the Th1/Th2 and Tc1/Tc2 ratios were significantly lower (P = 0.0305 and 0.0005, respectively) and returned to normal levels after treatment. In patients with acute brucellosis, serum sIL-2Rα levels were negatively correlated with the Th1/Th2 ratio (r = − 0.478, P = 0.028), Tc1/Tc2 ratio (r = − 0.677, P = 0.001), and Tc1 percentage (r = − 0.516, P = 0.017). Serum sIL-2Rα and Tc2 percentages were positively correlated (r = 0.442, P = 0.045).ConclusionsBased on the correlations with Th1/Th2 and Tc1/Tc2 ratios, serum sIL-2Rα levels may reflect the immune response status. sIL-2Rα may be a marker for therapeutic efficacy in acute brucellosis.

Urinary suPAR: a non-invasive biomarker of infection and tissue inflammation for use in studies of large free-ranging mammals.

Studies of large free-ranging mammals incorporating physiological measurements typically require the collection of urine or faecal samples, due to ethical and practical concerns over trapping or darting animals. However, there is a dearth of validated biomarkers of immune activation and inflammation that can be measured non-invasively. We here evaluate the utility of urinary measurements of the soluble form of the urokinase plasminogen activator receptor (suPAR), for use as a health marker in studies of wild large mammals. We investigate how urinary suPAR concentrations change in response to viral infection and surgical trauma (inflammation), comparing it to the measurement of a marker of cellular immune activation, urinary neopterin (uNEO), in captive rhesus macaques. We then test the field utility of urinary suPAR, assessing the effects of soil and faecal contamination, sunlight, storage at different temperatures, freeze–thaw cycles, and lyophilization. We find that suPAR concentrations rise markedly in response to both infection and surgery-associated inflammation, unlike uNEO concentrations, which only rise in response to the former. Our field validation demonstrates that urinary suPAR is reasonably robust to many of the issues associated with field collection, sample processing, and storage, as long as samples can be stored in a freezer. Urinary suPAR is thus a promising biomarker applicable for monitoring various aspects of health in wild primates and potentially also other large mammals.

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3).

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

Serum Neopterin in Differential Diagnosis of Bacterial Diarrhea in Pediatric Patients

Abstract Background: Neopterin, regarded as a marker of cellular immune activation, has been used in diagnosis of infection caused by intracellular pathogens. We have aimed to evaluate the clinical usefulness of serum neopterin (NPT) in acute bacterial diarrhea caused by group C enteropathogenic Escherichia coli (EPECs) and group D Salmonella spp. Methods: Serum concentration of NPT was determined by ELISA. The study group included 47 children with diagnosis of bacterial diarrhea: 32 caused by group C enteropathogenic Escherichia coli (EPECs) and 15 by group D Salmonella spp. 105 healthy children constituted the control group. Results: Serum concentration of NPT in children infected with group D Salmonella spp. turned out to be higher than in the other groups. The fraction of Salmonella-infected patients with serum neopterin above 11 nmol/l proved higher as compared to children with diarrhea caused by group C EPECs or to the healthy controls. The prevalence of a C-reactive protein (CRP) to NPT ratio of greater than 1 did not differ significantly between children with diarrhea of various etiology. Conclusions: Neopterin can be used as a non-specific marker differentiating between bacterial diarrhea of various etiology.

Red blood cell distribution width as an easily measurable biomarker of persistent inflammation and T cell dysregulation in antiretrovirally treated HIV-infected adults

Background: Chronic inflammation and immune dysfunction occur in human immunodeficiency virus (HIV)-infection despite stable antiretroviral therapy (ART). Red blood cell distribution width (RDW) has been shown to correlate with markers of inflammation in non-HIV conditions. The study objective was to determine associations between RDW with cellular markers of immune activation and immune dysfunction including soluble inflammatory mediators in ART treated HIV infection.Methods: We performed a cross-sectional analysis of the Hawaii Aging with HIV-Cardiovascular study. RDW was defined as one standard deviation of RBC size divided by mean corpuscular volume multiplied by 100%. Correlations were analyzed between RDW, soluble inflammatory biomarkers and T cell activation (CD38 + HLA-DR+), senescence (CD28-CD57+), and immune exhaustion (PD-1, TIGIT, TIM-3 expression).Results: Of 158 participants analyzed, median age was 50 years, duration of ART 12.6 years, virally suppressed 84.4%, and CD4 count 503 cells/mm3. Significant positive correlations were identified between RDW and soluble biomarkers including sICAM, IL-8, IL-6, SAA, TNF-α, sE-selection, fibrinogen, D-dimer, CRP, CD4/CD8 ratio, and frequency of multiple CD8 T-cell populations such as CD38 + HLA-DR + T-cells, single TIGIT+, and dual expressing of TIGIT + PD1+, TIGIT + TIM3+, and TIM3 + PD1+ CD8+ T-cell subsets (p < .05). Frequencies of CD38 + HLA-DR + CD8+ T-cells and TIGIT + CD8+ T-cells remained significant adjusting for baseline variables (p < .01).Conclusion: Our study revealed correlations between RDW with systemic inflammatory biomarkers and CD8+ T-cell populations related to immune activation and exhaustion in HIV-infected individuals on ART. Further studies are warranted to determine the utility of RDW as a marker of immune dysregulation in HIV.

The effect of switching protease inhibitors to raltegravir on endothelial function, in HIV-infected patients

ObjectiveLipid management is one of the cornerstones of cardiovascular risk reduction. Treatment of HIV infection with protease inhibitors (PIs) may cause dyslipidaemia, whilst the integrase inhibitor raltegravir (RAL) has a relatively favorable effect on plasma lipids. We examined the effect of switching from PIs to RAL on endothelial function, and its effect on immunological and inflammatory parameters.MethodsWe performed a 16-week open-label prospective crossover study: 8 weeks intervention (switch PIs to RAL) and 8 weeks control (unchanged cART regimen). Flow-mediated dilatation (FMD), inflammatory plasma, and cellular markers of immune activation were measured at weeks 0, 8, and 16.ResultsStudy participants (n = 22) with a median age of 50 years (IQR 42–60) and known HIV infection of 6.5 years (IQR 5.0–17.3) were on stable cART with undetectable HIV viral loads. After 8 weeks of RAL therapy, a reduction in FMD of −0.81% was seen, compared to +0.54% control (pairwise, p = 0.051), while fasting total cholesterol (−17% versus +10%; p < 0.001), LDL cholesterol (−21% versus −3%; p = 0.026), and triglycerides (−41% versus +18%; p = 0.001) significantly decreased during RAL therapy compared to the control.Furthermore, a relation between the change in percentage of B-1 cells and the change in FMD was found (β 0.40, 95%CI 0.16; 0.64, p = 0.005) during treatment with RAL. Finally, during RAL therapy, 27% of the patients experienced an increased ALT rise.ConclusionsWe present an overall negative study, where switching from PIs to RAL slightly reduced the endothelial function while decreasing plasma lipids, thus possibly decreasing the CVD risk in the long term. A transient elevation of ALT was seen upon switch to RAL.

Total sleep time and kynurenine metabolism associated with mood symptom severity in bipolar disorder.

Chronic, low-level inflammation is associated with symptomatic bipolar disorder (BD) and with chronic insomnia. Disrupted sleep is a feature of episodes of both mania and depression. We examined the effect of neopterin, a marker of cellular immune activation, and kynurenine (KYN), an inflammatory byproduct of the serotonin pathway, on the association between total sleep time and depression severity in BD. Twenty-one symptomatic BD participants and 28 healthy controls (HC) were recruited and followed during usual clinical care. At baseline and after symptomatic recovery, total sleep time was objectively measured with actigraphy for 1week and blood plasma was collected to measure the serotonin precursor tryptophan (TRP), KYN, the KYN/TRP ratio, and neopterin levels. Statistical analyses were conducted using chi-square, independent t tests and hierarchical linear multiple regression models. Total sleep time was correlated positively with depressive severity and negatively with manic severity. TRP was significantly reduced in BD participants compared to HC. KYN, TRP, and the KYN/TRP ratio were associated with depressive severity when total sleep time and body mass index (BMI) were included in the model. The KYN/TRP ratio trended towards a negative association with mania symptoms, controlling for BMI and total sleep time, in acutely symptomatic BD participants. Neopterin was not associated with sleep or mood severity. After usual clinical care, BD participants showed significantly decreased clinical symptoms but no significant differences in sleep phenotype or biomarkers. Inflammation, sleep, and mood are closely intertwined. Future research into the effect of inflammation on sleep in BD may lead to clinical markers of outcome.

Analysis of serum markers of cellular immune activation in patients with bullous pemphigoid.

Experimental models of bullous pemphigoid (BP), the most frequent subepidermal autoimmune bullous disease, revealed that the immune response leading to blister formation represents an incompletely understood complex process involving different inflammatory cells. In contrast to previous reports commonly focusing on limited molecular and cellular phenotypes of the disease, the aim of this study was to investigate a broad spectrum of markers of cellular immune activation in patients with BP. We found that serum levels of soluble CD4, myeloperoxidase, S100A12, eosinophil cationic protein and soluble P-selectin were significantly elevated in patients with active BP compared with normal controls. Mast cell tryptase and neopterin serum levels significantly decreased at the time of clinical remission of the patients. Additionally, serum concentrations of soluble IL-2 receptor, mast cell tryptase and soluble P-selectin were significantly associated with levels of circulating anti-BP180 autoantibodies. Our findings confirm and extend previous reports suggesting some concomitant involvement of a panel of molecules representative for a wide spectrum of cellular players (T cells, mast cells, neutrophils, eosinophils, macrophages and platelets) orchestrating the inflammatory reaction in BP. These data may favour the employment of broad-spectrum or combined immunosuppressants, potentially together with an anticoagulant treatment, over cell- or molecule-specific targeted therapy in patients with this disorder.

Age, but not anthelmintic treatment, is associated with urinary neopterin levels in semi-free ranging Barbary macaques

Studying host parasite interactions and their implications for evolution and ecology recently received increasing attention, particularly with regard to host physiology and immunity. Here we assess variation of urinary neopterin (uNEO), a marker of cellular immune activation and iummunosenescence, in response to age and anthelmintic treatment in semi-free ranging Barbary macaques (Macaca sylvanus). Urinary NEO levels were measured via enzyme-immunoassay from 179 urine samples of 43 individuals between 5–29 years of age. Efficiency of treatment was assessed by Mc Master flotation on repeated faecal samples, including 18 untreated individuals as control group. We used linear mixed models with age and parasite status as main effects, controlling for sex and physical condition, assessed through urinary C-Peptide-levels, with social group and ID as random factors. Urinary NEO levels significantly increased with age, suggesting that changes in aging Barbary macaque immune responses are consistent with immunosenescence described in human and nonhuman primates and can be detected via uNEO measurements. Anthelmintic treatment, however, had no influence on uNEO levels, potentially due to quick reinfections or attenuated immune responses in repeated infections. We conclude that uNEO is a potential non-invasive marker for immune function and particularly immunosenescence in wildlife.

HIV viral kinetics and T cell dynamics in antiretroviral naïve persons starting an integrase strand transfer inhibitor and protease inhibitor regimen

Background: Nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens may potentially minimize antiretroviral (ART) toxicities, but demonstrate mixed efficacy and toxicity results. The impact of an integrase strand transfer inhibitor (INSTI) and protease inhibitor (PI) regimen on HIV viral dynamics and T cell kinetics remains underdescribed.Objective: To compare the effect of raltegravir + ritonavir boosted lopinavir (RAL + LPV/r) to efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) on HIV kinetics and T cell dynamics.Methods: Fifty participants naïve to ART underwent HIV viral kinetic sampling evaluated using biexponential mixed effects modeling. A subset of 28 subjects (with complete viral suppression) underwent flow cytometry and evaluation of soluble markers of inflammation at weeks 0, 4, and 48 of ART.Results: RAL + LPV/r compared to EFV/TDF/FTC resulted in a prolonged first phase viral decay rate (18 vs. 13 days p < 0.01). From weeks 0 to 4, RAL + LPV/r was associated with a trend toward greater decreases in activated CD4+ T cells (−3.81 vs. −1.18 p = 0.09) and less decreases in activated effector memory CD4+ T cells (−0.63 vs. −2.69 p-0.07). These trends did not persist to week 48. No differences were noted at any time point for soluble markers of immune activation.Conclusions: The prolonged first phase viral decay observed with RAL + LPV/r in persons starting ART did not result in differences in viral suppression at week 48. We also observed trends in declines in certain cellular markers of immune activation but it remains unclear if this could translate to long-term immunologic benefits in persons on an INSTI + PI.

Maraviroc Intensification Improves Endothelial Function in Abacavir-Treated Patients, an Open-Label Randomized Cross-Over Pilot Study

BackgroundThe increased risk of abacavir in cardiovascular disease (CVD) in HIV-infected patients is still being debated. Maraviroc, a CCR5 blocker, has been shown to decrease immune activation and monocyte infiltration in atherosclerotic plaques in murine experiments. Therefore, we examined the effect of maraviroc intensification on flow-mediated dilatation (FMD) in abacavir-treated HIV-infected patients and its effect on immunological and inflammatory parameters.MethodsA open-label prospective crossover study with a duration of 16 weeks: 8 weeks of intervention (maraviroc intensification) and 8 weeks of control (unchanged cART regimen). FMD, HIV-specific variables, expression of HIV co-receptors, markers of inflammation and coagulation and cellular markers of immune activation were measured at weeks 0, 8 and 16. The changes (Δ) in these variables were compared between intervention and control periods using non-parametric tests. To evaluate the relation with the change in FMD, linear regression modeling was used.ResultsTwenty-one male patients with suppressed plasma HIV-RNA, on cART, had a known HIV infection for 9.2 years (IQR 6.9–13.5) with abacavir use for 6.5 years (2.8–9.3). A significantly increased FMD of 0.73% (IQR −0.25 to 1.70) was seen after maraviroc intensification compared to a decrease of −0.42% (IQR −1.89 to 0.25; p = 0.049) in the control period. There was a negative relation between ΔFMD with ΔD-dimer (β −22.70, 95% CI −39.27; −6.13, p = 0.011) and ΔCD95+ CD4+ T cells (β −0.16, 95% CI −0.28; −0.04, p = 0.013), adjusted for age and duration of HIV.ConclusionMaraviroc intensification modestly improves endothelial function in HIV-infected patients on an abacavir-containing regimen.Trial registrationNCT01389063.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-016-0115-0) contains supplementary material, which is available to authorized users.

Maternal plasma total neopterin and kynurenine/tryptophan levels during pregnancy in relation to asthma development in the offspring

Neopterin levels and kynurenine/tryptophan ratios (KTRs) increase with IFN-γ stimulation, indicating TH1 immunity, and thus might be inversely associated with asthma. We sought to examine the association of maternal neopterin levels and KTRs during pregnancy with asthma in the offspring. We analyzed the associations of maternal plasma total neopterin levels and KTRs in midpregnancy with asthma at age 7years among 2883 children in the Norwegian Mother and Child Cohort Study. Asthma was classified either based on registered dispensed asthma medications in the Norwegian Prescription Database or maternal report. We calculated adjusted relative risks using log-binomial regression. The median gestational week of blood sampling was 18weeks (interquartile range, 17-19weeks). The risk of dispensed asthma medications at age 7years was highest among children of mothers in the highest quartile of neopterin levels, whereas the risk was similar in the 3 lowest quartiles. The adjusted relative risk of dispensed asthma medications was 1.66 (95% CI, 1.16-2.38) when comparing children of mothers in the highest quartile with those in the 3 lowest quartiles. Asimilar association was observed for maternal report of asthma at age 7years. When we evaluated allergic versus nonallergic asthma, neopterin levels tended to be associated with nonallergic asthma. Maternal KTR was not associated with asthma development. Our findings indicate that high maternal levels of neopterin, a marker of cellular immune activation, during pregnancy were positively associated with asthma in offspring. Experimental studies would be needed to further elucidate underlying mechanisms.

HIV vasculopathy: role of mononuclear cell-associated Krüppel-like factors 2 and 4.

To determine the relationships between Krüppel-like factors (KLF) 2 and 4, immune-activation, and subclinical vascular disease in HIV-infected patients on antiretroviral therapy (ART). Double-blind, randomized, placebo-controlled trial. We studied 74 HIV-infected adults on ART enrolled in a randomized clinical trial of statin therapy. KLF2 and KLF4 gene expression was measured by quantitative PCR from peripheral blood mononuclear cells (PBMCs) at baseline and after 24 weeks of 10 mg daily rosuvastatin or placebo. At the same time points, T-cell and monocyte activation were assessed by flow cytometry and vascular health was assessed by cardiac computed tomography and carotid ultrasound. KLF4 expression was negatively correlated with duration of ART (r = -0.351, P = 0.004) and positively correlated with measures of immune activation: proinflammatory monocytes [CD14CD16 (r = 0.343, P = 0.003)], patrolling monocytes [CD14CD16 (r = 0.276, P = 0.017)], and activated CD8 T-lymphocytes [CD8DRCD38 (r = 0.264, P = 0.023)]. KLF2 expression was negatively correlated with subclinical atherosclerosis: mean-mean common carotid artery intima-media thickness (r = -0.231, P = 0.048), mean-max carotid artery intima-media thickness (r = -0.271, P = 0.020), and coronary artery calcium score (r = -0.254, P = 0.029). There were no statistically significant changes in KLF2/4 expression in PBMCs after 24 weeks of rosuvastatin. Expression of KLF4 in PBMCs positively correlates with cellular markers of immune activation, whereas KLF2 expression negatively correlates with markers of subclinical atherosclerosis in this HIV-infected population on ART. Additional studies are needed to determine if targeted interventions might alter KLF2/4 expression to reduce inflammation and vascular risk in humans.

Abstract B23: Autoimmune hypophysitis is a marker of favorable outcome during treatment of melanoma with ipilimumab

Abstract Introduction: Autoimmune hypophysitis (AH) is an immune-related adverse effect (ir-AE) of the human IgG1 monoclonal antibody ipilimumab. Evidence suggests AH is mediated by complement deposition in adenohypophyseal cells expressing cytotoxic T lymphocyte antigen-4 (CTLA-4). Despite increasing incidence, AH remains poorly characterized. We conducted a retrospective cohort study of melanoma subjects treated with ipilimumab, with the primary objective to characterize AH and examine its association with overall survival (OS). Methods: Inclusion criteria: stage 3/4 cutaneous, ocular, or mucosal melanoma at a single institution, treated with ipilimumab between 2005 and 2013. AH was defined as primary hypopituitarism clinically diagnosed by endocrinologist or cutaneous oncologist. Baseline BMI and laboratory values were collected within 30 days prior to first dose. Overall survival (OS) was defined as time from first dose to death of any cause. Time-to-progression (TTP) was defined as time from first dose to any objective progression event, and censored if &amp;gt;4 months (mo) elapsed between evaluations to ensure homogenous follow-up time. Statistical tests were non-parametric and 2-sided. Results: Of 295 patients screened, 269 were eligible (32 AH+, 237 AH-). Demographics at first dose: median age 61.6, 35% female, 99.3% white, 1.9% Hispanic, mean body mass index (BMI) 28 kg/m2, mean lactate dehydrogenase (LDH) 644 IU/L, mean albumin 4.0 mg/dL, mean absolute lymphocyte count 1.39 x 103/μL. For TNM stage, 65% M1c, 14% M1b, 6% M1a, 15% M0. At time of first dose, 29.5% were resected no evidence-of-disease (NED). Of 132 (49%) with known allelic status, 38 (29%) were BRAF mutant. Median time-to-AH was 2.8 mo (range 0.9 – 18.7). Initial dose of 10 mg/kg was associated with increased AH risk (RR 1.2, p=0.002). Presenting symptoms included fatigue (58%), headache (33%), nausea (24%). Lab findings at diagnosis (median, range): ACTH 7.0 (1-26), cortisol 2.2 (0-29.7), TSH 0.34 (0-3.9), T4 0.7 (0.3 – 3.6), FSH 7.0 (1.1 – 41), LH 0.7 (0.2 – 20.5). 17 of 30 evaluable subjects had abnormal pituitary identified on MRI. All were administered exogenous corticosteroids and 72% required exogenous thyroid supplementation. 13% eventually recovered endogenous pituitary function. There was no association with prior endocrine conditions or other ir-AEs. For evaluable subjects, AH also seemed to have favorable objective response rate, although this was not statistically significant (p=0.20). Median follow-up duration was 43.7 mo, median OS was 20.3 mo, and median TTP was 5.2 mo. AH was associated with superior OS (HR 0.4, 95% CI 0.3 – 0.7, p=0.001) and TTP (HR 0.4, 95%CI 0.3- 0.8, p=0.0002). Using Landmark analysis to avoid bias from immortal person-time, after 4 cycles of ipilimumab, AH remained associated with OS (HR 0.5, p=0.04). Using the alternative Crowley method, similar results were seen for both OS (HR 0.5, p=0.002) and TTP (HR 0.6, p=0.005). AH was then examined as a time-dependent covariate in Cox regression. On univariate analysis, LDH, M-stage, resected NED, albumin, age, absolute lymphocyte count, and AH were significantly associated with OS (p &amp;lt;0.01 for all). Similar findings were found for TTP. After including a propensity score regression term to control for all known confounders (LDH, albumin, BMI, lymphocyte count, M-stage, NED, smoking, race, age, gender), AH remained an independent predictor for improved OS (HR 0.49;95%CI 0.24-0.98; p=0.04). Conclusion: Hypophysitis appears to predict benefit from ipilimumab treatment, possibly since it may serve as a marker of cellular immune activation. Independent validation of these results in external cohorts is required. Citation Format: Jennifer M. Eatrides, Jeffrey Weber, Kathleen Egan, Marjorie Acierno, Michael Schell, Howard Lillienfeld, Ben Creelan. Autoimmune hypophysitis is a marker of favorable outcome during treatment of melanoma with ipilimumab. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B23.