Macrophage-derived Chemokine Levels Research Articles

Abstract 6642: Exploring the x-ray psoralen activated cancer therapy mechanism of action in a genetically engineered mouse model of soft tissue sarcoma

Abstract BACKGROUND: Psoralen is a natural ultraviolet activated compound that has been used for over 70 years to treat skin cancer, psoriasis, and vitiligo. Recently, to expand its use beyond external treatment, a novel therapeutic called X-PACT (X-ray psoralen activated cancer therapy) was created to treat internal tumors. A combination of 8-methoxypsoralen and phosphors that convert low doses of x-ray radiation to ultraviolet (UV) light are injected into solid tumors and subsequently activated by x-ray photons with considerable antineoplastic effect. Notably, canine clinical trials have observed significant abscopal effects of X-PACT therapy on metastatic lesions throughout patients, but the immunomodulatory mechanisms of action are unclear (Nolan et al, in submission). Here, we present preliminary data investigating the immune response to X-PACT therapy in a murine soft tissue sarcoma (STS) model. METHODS: Six mice of the inducible KrasG12D/+; p53flox/flox (KP) murine STS model with palpable, gastrocnemius tumors were used in this initial study. Four mice underwent treatment with X-PACT. In this group, psoralen was mixed with energy converters and injected into the tumor. The mice then received low-level radiation to activate the drug. Treatment was performed five times over a 15-day period and the animals were sacrificed within 48 hours of final treatment. The other two mice with induced tumors received no treatment prior to sacrifice. For both groups, a cardiac blood draw was performed at the time of sacrifice to obtain plasma serum for analysis. Luminex xMAP technology was used for multiplexed quantification of 45 mouse cytokines, chemokines and growth factors. RESULTS: There were five markers that showed significantly different levels between the treated and control groups. Results indicated significantly higher (p = 0.006) plasma concentrations of macrophage derived chemokine (MDC) following five rounds of treatment with X-PACT therapy. Additionally, the treated mice displayed significantly lower concentrations of granulocyte colony-stimulating factor (G-CSF, p = 0.003), eotaxin (p = 0.016), tissue inhibitor of matrix metalloproteinase 1 (TIMP1, p = 0.024), and interleukin-1β (IL-1β, p = 0.033) compared to untreated mice with STS. CONCLUSION: In humans, MDC levels are associated with longer survival and lower cancer severity. G-CSF, eotaxin, TIMP1, and IL-1β are upregulated in cancer patients and correlate with disease severity. Together, the lower concentrations of G-CSF, Eotaxin, TIMP1, and IL-1β suggest a softening of cancer severity following X-PACT treatment. Further studies and larger sample sizes are necessary to confirm and expand upon these preliminary findings. Citation Format: Beatrice Schleupner, Alexandra Hunter Aitchison, Elle MacAlpine, Nicole Cantor, Jason Somarelli, Brian Brigman, Julia Visgauss, Michael Monument, William Eward. Exploring the x-ray psoralen activated cancer therapy mechanism of action in a genetically engineered mouse model of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6642.

A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives

AimsSubstantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. MethodsIn a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. ResultsCompared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12–1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09–1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04–1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02–1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC.Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75–0.77) ConclusionsHigher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD.

Low-grade inflammation in type 2 diabetes: a cross-sectional study from a Danish diabetes outpatient clinic

ObjectivesTo investigate low-grade inflammation in type 2 diabetes and explore associations to clinical aspects as well as microvascular and macrovascular complications.DesignCross-sectional analysis.SettingThe outpatient diabetes clinic at the Department of Endocrinology...

Endogenous Adenosine 5'-Monophosphate, But Not Acetylcholine or Histamine, is Associated with Asthma Control, Quality of Life, and Exacerbations.

Endogenous adenosine 5'-monophosphate (AMP), acetylcholine (ACh), and histamine (HA) are known to be important in bronchial contraction, but their clinical relevance to asthma is poorly understood. We aimed to quantify endogenous AMP, ACh, and HA in induced sputum samples and explore their relationships with asthma control and exacerbations. 20 healthy subjects and 112 asthmatics underwent clinical assessment, sputum induction, and blood sampling. The level of asthma control was determined by the asthma control test (ACT) questionnaire. Asthma exacerbation was evaluated according to the criteria of the American Thoracic Society/European Respiratory Society. Levels of AMP, ACh, and HA in sputum were measured by liquid chromatography coupled to tandem mass spectrometry. IL-β, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17A, TNF-α, IFN-γ, and macrophage-derived chemokine (MDC) were also measured. Compared to healthy controls, asthmatics had higher levels of HA, lower levels of ACh, and similar levels of AMP in induced sputum samples. Compared to controlled asthma (n=54), uncontrolled asthma (n=58) showed higher AMP levels (P=0.002), but similar HA and ACh levels. AMP was negatively correlated with ACT scores (r=-0.348) and asthma quality of life questionnaire scores (r=-0.188) and positively correlated with blood monocytes percentage (r=0.195), sputum MDC (r=0.214), and IL-6 levels (r=0.196). Furthermore, AMP was associated with an increased risk of exacerbations in the preceding year. Endogenous AMP, but not ACh or HA, was associated with asthma control, quality of life, and exacerbations in the previous year, which indicates that AMP could be a clinically useful biomarker of asthma.

Anti-inflammatory effects of ethanol extract from the leaves and shoots of Cedrela odorata L. in cytokine-stimulated keratinocytes.

Cedrela odorata L. is a native plant of the Amazon region. The bark is used in folk remedies for the treatment of diarrhea, vomiting, fever and inflammation. Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease accompanied by itching. It is a complex disease involving environmental factors and genetic factors. In the present study, the anti-inflammatory and anti-allergic effects of C. odorata L. methanol extract (COEE) on tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated HaCaT keratinocyte cells were investigated. ELISA and RT-PCR analysis revealed that the extract had anti-inflammatory effects, and reduced the interleukin (IL)-6 and IL-8 levels of the HaCaT cells. In addition, COEE exhibited anti-allergic effects, comprising a reduction in the thymus and activation-regulated chemokine and macrophage-derived chemokine levels. In addition, pathway analysis and comparison with Bay11-7082 indicated that these effects are due to the inhibition of nuclear factor (NF)-κB in TNF-α/IFN-γ-induced HaCaT cells. Therefore, the results of the present study suggest that COEE has anti-inflammatory and anti-allergic properties in TNF-α and IFN-γ-stimulated HaCaT cells, which are associated with the inhibition of pro-inflammatory cytokines and chemokines via the NF-κB pathway.

Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study

AbstractSerum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)–positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Inflammatory and regulatory CCL and CXCL chemokine and cytokine cellular responses in patients with patent Mansonella perstans filariasis.

Mansonella perstans (Mp) filariasis is present in large populations in sub-Saharan Africa, and to what extent patent Mp infection modulates the expression of immunity in patients, notably their cellular cytokine and chemokine response profile, remains not well known. We studied the spontaneous and inducible cellular production of chemokines (C-X-C motif) ligand 9 (CXCL9) [monokine induced by interferon (IFN)-γ (MIG)], CXCL-10 [inducible protein (IP)-10], chemokine (C-C motif) ligand 24 (CCL24) (eotaxin-2), CCL22 [macrophage-derived chemokine (MDC)], CCL13 [monocyte chemotactic protein-4 (MCP-4)], CCL18 [pulmonary and activation-regulated chemokine (PARC)], CCL17 [thymus- and activation-regulated chemokine (TARC)] and interleukin (IL)-27 in mansonelliasis patients (Mp-PAT) and mansonelliasis-free controls (CTRL). Freshly isolated peripheral mononuclear blood cells (PBMC) were stimulated with helminth, protozoan and bacterial antigens and mitogen [phytohaemagglutinin (PHA)]. PBMC from Mp-PAT produced spontaneously (without antigen stimulation) significantly higher levels of eotaxin-2, IL-27, IL-8, MCP-4 and MDC than cells from CTRL, while IFN-γ-IP-10 was lower in Mp-PAT. Helminth antigens activated IL-27 and MCP-4 only in CTRL, while Ascaris antigen, Onchocerca antigen, Schistosoma antigen, Entamoeba antigen, Streptococcus antigen, Mycobacteria antigen and PHA stimulated MIG release in CTRL and Mp-PAT. Notably, Entamoeba antigen and PHA strongly depressed (P<0·0001) eotaxin-2 (CCL24) production in both study groups. Multiple regression analyses disclosed in Mp-PAT and CTRL dissimilar cellular chemokine and cytokine production levels being higher in Mp-PAT for CCL24, IL-27, IL-8, MCP-4, MDC and PARC (for all P<0·0001), at baseline (P<0·0001), in response to Entamoeba histolytica strain HM1 antigen (EhAg) (P<0·0001), Onchocerca volvulus adult worm-derived antigen (OvAg) (P=0·005), PHA (P<0·0001) and purified protein derivative (PPD) (P<0·0001) stimulation. In Mp-PAT with hookworm co-infection, the cellular chemokine production of CXCL10 (IP-10) was diminished. In summary, the chemokine and cytokine responses in Mp-PAT were in general not depressed, PBMC from Mp-PAT produced spontaneously and selectively inducible inflammatory and regulatory chemokines and cytokines at higher levels than CTRL and such diverse and distinctive reactivity supports that patent M. perstans infection will not polarize innate and adaptive cellular immune responsiveness in patients.

Inflammatory cytokine profiles in eyes with primary angle-closure glaucoma.

Acute primary angle-closure (APAC) eyes show an early ‘acute inflammatory’ condition, while the inflammation condition has not been fully elucidated in the development of primary angle-closure glaucoma (PACG). To evaluate the roles of inflammatory cytokines in the pathogenesis of PACG, this cross-sectional study involved 40 eyes of 32 PACG patients who required trabeculectomy and 24 eyes of 24 patients who required cataract surgery. The aqueous humor samples were collected at the time of surgery. Fifteen inflammatory cytokines were detected using the multiplex bead immunoassay technique, and the clinical information was recorded for the correlation analysis. Eight of the 15 cytokines were all detectable in both groups, including granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, MCP-3, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1β, and vascular endothelial growth factor (VEGF). When compared with the cataract patients, the MCP-3, MDC, and VEGF levels were elevated in the PACG patients, while the MCP-1 and MIP-1β levels were decreased. However, the G-CSF, IL-6, and IL-8 levels were similar between the two groups. The MCP-1 concentration was elevated accordingly as the disease progressed in the PACG patients. Our results suggest the PACG eyes retained a ‘mild inflammation’ condition in the aqueous humor, and MCP-1 may play an important role in the progression of this disease.

Maternal Diet, Metabolic State, and Inflammatory Response Exert Unique and Long-Lasting Influences on Offspring Behavior in Non-Human Primates.

Nutritional status influences brain health and gestational exposure to metabolic disorders (e.g. obesity and diabetes) increases the risk of neuropsychiatric disorders. The aim of the present study was to further investigate the role of maternal Western-style diet (WSD), metabolic state, and inflammatory factors in the programming of Japanese macaque offspring behavior. Utilizing structural equation modeling, we investigated the relationships between maternal diet, prepregnancy adiposity, third trimester insulin response, and plasma cytokine levels on 11-month-old offspring behavior. Maternal WSD was associated with greater reactive and ritualized anxiety in offspring. Maternal adiposity and third trimester macrophage-derived chemokine (MDC) exerted opposing effects on offspring high-energy outbursts. Elevated levels of this behavior were associated with low maternal MDC and increased prepregnancy adiposity. This is the first study to show that maternal MDC levels influence offspring behavior. We found no evidence suggesting maternal peripheral inflammatory response mediated the effect of maternal diet and metabolic state on aberrant offspring behavior. Additionally, the extent of maternal metabolic impairment differentially influenced chemokine response. Elevated prepregnancy adiposity suppressed third trimester chemokines, while obesity-induced insulin resistance augmented peripheral chemokine levels. WSD also directly increased maternal interleukin-12. This is the first non-human primate study to delineate the effects of maternal diet and metabolic state on gestational inflammatory environment and subsequent offspring behavior. Our findings give insight to the complex mechanisms by which diet, metabolic state, and inflammation during pregnancy exert unique influences on offspring behavioral regulation.

Oxymatrine Sensitizes the HaCaT Cells to the IFN-γ Pathway and Downregulates MDC, ICAM-1, and SOCS1 by Activating p38, JNK, and Akt.

Decreased interferon (IFN)-γ levels and increased levels of macrophage-derived chemokine (MDC) and intercellular adhesion molecule (ICAM)-1 are known to be involved in allergic skin diseases, such as eczema and atopic dermatitis. Activation of the IFN-γ and its downstream interleukin-12 (IL-12) pathway can correct these diseases. Suppressor of cytokine signaling 1 (SOCS1) is a cytokine signaling inhibitor that blocks downstream pathways of IFN-γ by blocking the mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling pathways. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the herbal medicine Radix Sophorae flavescentis, is used to treat allergic skin diseases in China. The non-cytotoxic concentrations of OMT in HaCaT cells were determined through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Tumor necrosis factor (TNF)-α and IFN-γ were used to stimulate HaCaT cells, and OMT was added to this system with tacrolimus (FK506) as a positive control. The mRNAs of cytokines, MDC, ICAM-1, IL-12p35, IL-12p40, and IFN-γ receptor (IFN-γR)α were detected by RT-PCR. Western blot analyses were performed to assess activation of the MAPK (p38, Jun N-terminal kinase, and extracellular signal-regulated kinase) and Akt signaling pathways. OMT increased the mRNA levels of the IL-12 and IFN-γRα, reduced the mRNA levels of ICAM-1, MDC, and SOCS1. But FK506 increased the mRNA levels of IL12 and inhibited the expression of ICAM-1 mRNAs and had no effects on the IFN-γRα, MDC, and SOCS1 mRNA in HaCaT cells stimulated with TNF-α and IFN-γ. Thus, the mechanisms through which OMT and FK506 ameliorate allergic skin diseases differ.

Industrial hog farming is associated with altered circulating immunological markers

ObjectivesThe previously observed inverse association between hog farming and risk of lung cancer in the Agricultural Health Study (AHS) has been attributed to endotoxin exposure, the levels of which are...

Macrophage-Derived Chemokine: A Putative Marker of Pharmacological Therapy Response in Major Depression?

Introduction: Inflammatory processes play an important and complex role in the pathophysiology of major depressive disorder (MDD), but, so far, no specific investigation of chemokines exists. Methods: In this study, we investigated the changes of plasma chemokine levels (eotaxin-1, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, and TARC) in 47 MDD patients before (PRE) and after 1 and 6 weeks of pharmacological treatment (POST1 and POST6) in relation to the response to antidepressive therapy. We hypothesized that the direction of alterations in levels of chemokines would significantly differ between the 2 groups, responders and nonresponders. Results: Among the investigated chemokines, only the level of macrophage-derived chemokine (MDC) changed significantly in relation to therapy response. MDC levels were significantly elevated in the responder group at POST6. Discussion: MDC is a constitutively expressed chemokine involved in the pathophysiology of infectious and neoplastic diseases. This is the first study providing valuable hints that MDC might serve as a marker of pharmacological therapy response in MDD.

Effects of Proton and Combined Proton and (56)Fe Radiation on the Hippocampus.

The space radiation environment contains protons and (56)Fe, which could pose a significant hazard to space flight crews during and after missions. The space environment involves complex radiation exposures, thus, the effects of a dose of protons might be modulated by a dose of heavy-ion radiation. The brain, and particularly the hippocampus, may be susceptible to space radiation-induced changes. In this study, we first determined the dose-response effect of proton radiation (150 MeV) on hippocampus-dependent cognition 1 and 3 months after exposure. Based on those results, we subsequently exposed mice to protons alone (150 MeV, 0.1 Gy), (56)Fe alone (600 MeV/n, 0.5 Gy) or combined proton and (56)Fe radiations (protons first) with the two exposures separated by 24 h. At one month postirradiation, all animal groups showed novel object recognition. However, at three months postirradiation, mice exposed to either protons or combined proton and (56)Fe radiations showed impaired novel object recognition, which was not observed in mice irradiated with (56)Fe alone. The mechanisms in these impairments might involve inflammation. In mice irradiated with protons alone or (56)Fe alone three months earlier, there was a negative correlation between a measure of novel object recognition and the number of newly born activated microglia in the dentate gyrus. Next, cytokine and chemokine levels were assessed in the hippocampus. At one month after exposure the levels of IL-12 were higher in mice exposed to combined radiations compared with sham-irradiated mice, while the levels of IFN-γ were lower in mice exposed to (56)Fe radiation alone or combined radiations. In addition, IL-4 levels were lower in (56)Fe-irradiated mice compared with proton-irradiated mice and TNF-α levels were lower in proton-irradiated mice than in mice receiving combined radiations. At three months after exposure, macrophage-derived chemokine (MDC) and eotaxin levels were lower in mice receiving combined radiations. The levels of MDC and eotaxin correlated and the levels of MDC, but not eotaxin, correlated with the percentage of newly born activated microglia in the blades of the dentate gyrus. Finally, hippocampal IL-6 levels were higher in mice receiving combined radiations compared with mice receiving (56)Fe radiation alone. These data demonstrate the sensitivity of novel object recognition for detecting cognitive injury three months after exposure to proton radiation alone, and combined exposure to proton and (56)Fe radiations, and that newly-born activated microglia and inflammation might be involved in this injury.

A Phase II, Single-Center, Open-Label Study Of Oral Panobinostat In Combination With Lenalidomide and Weekly Dexamethasone In Patients With Multiple Myeloma

BackgroundTreatment options for patients with multiple myeloma (MM) refractory (ref) to lenalidomide (len) and bortezomib are urgently needed. A promising strategy is the use of epigenetic agents such as the deacetylase inhibitor (DACi) panobinostat (pan) to modulate genes that affect drug resistance. Pre-clinical studies with pan demonstrated synergy against MM cells when combined with dexamethasone (dex) and len, supporting this concept (Ocio EM et al. Haematologica 2010).The safety and preliminary efficacy of this triplet regimen was assessed in a phase 1b study of relapsed (rel) or rel/ref MM patients (Mateos et al, ASCO 2010). The maximum tolerated doses (MTD) in that study are the doses selected for this phase 2 study. However we investigated a modified schedule (table 1) of this triplet regimen. Here, pan is given thrice weekly only every other week (instead of weekly) and dex is given weekly (instead of three 4 day pulses).To investigate the hypothesis that peripheral blood plasma levels of cytokines/chemokines known to be elevated in MM patients may identify biomarkers of response to this regimen, we examined IL-6, IL-10, IL-17A, Monocyte Chemoattractant Protein (MCP)-1 and Macrophage Derived Chemokine (MDC) levels at baseline and following 4 cycles of treatment. Patients and MethodsInclusion criteria were patients with rel or rel/ref MM, measurable disease, adequate performance status, organ function, and hematologic parameters. Patients previously treated with a DACI or currently receiving medications with a risk of prolonging the QTc interval were excluded.The primary objective was to evaluate the best overall response rate. Secondary objectives were to evaluate safety, response duration, and overall and progression-free survival. Each drug was administered at the doses and schedule shown in Table 1.Table 1Study Drug DosesPanobinostatLenalidomideDexamethasone20 mg po Day 1, 3, 5, 15, 17,1925 mg po Day 1-2140 mg po Day 1, 8, 15 ResultsOverall, 5 len-refractory patients with disease progression at screening have been enrolled. Patients had a median of 2 lines of prior therapy (range 1–7). High-risk molecular findings were present in 3 patients, including 2 patients with gain of 1q21 by FISH and 1 with del p53.Very good partial response (VGPR) was achieved in 1/5, partial response (PR) in 1/5, minimal response (MR) in 1/5, and stable disease (SD) in 2/5. Two of these high-risk patients are still on study, and the patient with del p53 had PD at 4 months. Responses are durable, with 3 patients (including both patients with ≥PR) remaining on study for more than 4 months, with a median follow up of 4 months. Two patients progressed within 4 months.Grade 3 and 4 toxicities (regardless of drug attribution) were primarily hematologic, with neutropenia, thrombocytopenia, and anemia noted in 3, 3, and 1 patient(s) respectively. There were 2 serious adverse events (SAEs) – a grade 3 pulmonary embolism and febrile neutropenia (FN) due to N. meningitidisbacteremia. The non-hematologic toxicities were all grade 1 and 2, consisting of fatigue in 5 patients and diarrhea in 2. Dose modifications were required in 2 patients for len and 2 patients for pan, 1 for FN and the other for asymptomatic T wave inversions.Cytokine profiling revealed that MDC was reduced by 48%, 7% and 72% respectively in all 3 patients having a durable response (>4 months) following therapy. Of note, Thymus Activation-Regulated Chemokine (TARC) was identified as a biomarker of treatment response to pan in lymphoma patients (Harrison et al. Leuk Lymphoma 2013). Both MDC and TARC bind to the chemokine receptor CCR4 and are located on chromosome 16q13. MDC promotes angiogenesis and alters T cell distribution in the bone marrow. These findings suggest a link between DACi and CCR4 receptor ligand MDC levels. Thus, MDC may be a biomarker of sustained response to pan in MM and warrants further investigation. ConclusionsIn rel/ref MM patients, pan in combination with len and dex demonstrates durable responses, even in len-refractory patients with high-risk molecular findings, indicating the essential role of pan in attaining a response. These results suggest that pan modulates expression of genes to restore sensitivity to len, and that MDC may be a biomarker of this activity. This completely oral regimen is well tolerated, with primarily expected hematologic toxicities. Updated results will be presented at the annual meeting. Disclosures:Jagannath:Celgene: Honoraria; Millenium: Honoraria. Chari:Onyx: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005). The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

Elevated serum levels of macrophage-derived chemokine and thymus and activation-regulated chemokine in autistic children

BackgroundIn some autistic children, there is an imbalance of T helper (Th)1/Th2 lymphocytes toward Th2, which may be responsible for the induction of the production of autoantibodies in these children. Th2 lymphocytes express CCR4 receptors. CCR4 ligands include macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC). They direct trafficking and recruitment of Th2 cells. We are the first to measure serum levels of CCR4 ligands in relation to the degree of the severity of autism.MethodsSerum concentrations of MDC and TARC were measured, by quantitative sandwich enzyme immunoassay technique, in 56 autistic children and 32 healthy matched children.ResultsAutistic children had significantly higher serum levels of MDC and TARC than healthy controls (P <0.001 and P <0.001, respectively). Children with severe autism had significantly higher serum levels of MDC and TARC than patients with mild to moderate autism (P <0.001 and P = 0.01, respectively). In addition, there were significant positive correlations between CARS and serum levels of both MDC (P <0.001) and TARC (P <0.001) in children with autism. There were significant positive correlations between serum levels of MDC and TARC in autistic children (P <0.001).ConclusionsSerum levels of CCR4 ligands were elevated in autistic children and they were significantly correlated to the degree of the severity of autism. However, further research is warranted to determine the pathogenic role of CCR4 ligands in autism and to shed light on the therapeutic role of CCR4-ligand antagonism in autistic children.

Modulation of cardiometabolic pathways in skin and serum from patients with psoriasis

BackgroundModerate-to-severe psoriasis is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD); however, the link is poorly understood.MethodsSkin and serum from patients with psoriasis were evaluated to understand if there was evidence of dysregulation in a targeted group of inflammatory and lipid genes related to ASCVD. Microarray analyses of expression of targeted ASCVD genes from skin in 89 patients with moderate-to-severe psoriasis from the ACCEPT trial were compared with non-diseased skin from healthy controls (n = 25). Serum (n = 149) was tested at baseline for monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine (MDC), and apolipoprotein-A1 (Apo-A1) comparing to healthy controls (n=162).ResultsAn increase in skin gene expression for MCP-1 (7.98-fold) and MDC (6.66-fold) (p < 0.001 each) was observed in lesional versus healthy skin. Significant decreases in liver X receptor-alpha (LXR-α) (−5.94-fold), a protective lipoprotein metabolism gene, and in peroxisome proliferator-activated receptor-alpha (PPAR-α) (−7.58-fold), a protective anti-inflammatory and lipid modulating gene, were observed in lesional versus healthy skin (p < 0.001 each). Serum analyses revealed that MCP-1 (502 vs. 141 pg/mL) and MDC (1240 vs. 409 pg/mL) levels were significantly elevated in psoriasis compared with healthy controls (p < 0.001 each). Dysregulated lipid metabolism was also evident in the serum, as Apo-A1, a protein product related to PPAR-α activation, was significantly decreased in patients with psoriasis compared with healthy controls (25.2 vs. 38.9 mg/dL; p < 0.001).ConclusionsAnalyses of targeted genes and their products known to be associated with ASCVD revealed dysregulation of inflammatory (MCP-1 and MDC) and lipid metabolism (LXR-α, PPAR-α) genes in psoriasis. These findings provide evidence of a potential shared pathophysiology linking psoriasis to cardiometabolic diseases.

481: Maternal-fetal cellular trafficking and fetal inflammation in patients with preterm premature rupture of membranes

inflammation in patients with preterm premature rupture of membranes Dana Henry, Yvonne Cheng, Payam Saadai, Sheila Keating, Tzong-Hae Lee, Philip Norris, Michael Busch, Roberto Romero, Tippi MacKenzie UCSF, Obstetrics and Gynecology, San Francisco, CA, UCSF, Surgery, San Francisco, CA, Blood Systems Research Institute, Blood Bank, San Francisco, CA, Hutzel Women’s Hostpial, Obstetrics and Gynecology, Detroit, MI OBJECTIVE: Maternal-fetal cellular trafficking (MFCT) is the bidirectional passage of cells between the mother and her fetus. We previously reported alterations in trafficking after fetal surgery but the extent of MFCT in preterm premature rupture of membranes (PPROM) has not been characterized. We studied MFCT and changes in potential biomarkers in maternal and umbilical cord blood in PPROM. STUDY DESIGN: We prospectively obtained matched maternal and umbilical cord blood samples from 23 healthy term control patients and 13 patients with PPROM. The extent of MFCT was determined using PCR for non-shared HLA-DR alleles. “High traffickers” were defined as those above the 75th percentile of control patients. Serum cytokine and chemokine levels were analyzed using a human 39plex immunoassay system (Millipore). RESULTS: The gestational age at delivery was lower in patients with PPROM than in the control group (33.1 vs. 39.5 wks, p 0.01 by t-test). High trafficking of maternal cells into cord blood was more common in patients with PPROM than in those in the control group (60% vs. 23%, P 0.007 by Chi-square test), while trafficking of fetal cells in maternal blood was unchanged. Fetal levels of Flt-3 ligand, IL-1 , IL-1R , IL-10, monocyte chemotactic protein-1, and sIL-2R were significantly higher in PPROM, while levels of macrophage-derived chemokine were significantly lower (p 0.05 by Kruskal-Wallis). Maternal levels of IL-6 and IL-10 were increased and levels of eotaxin were decreased in PPROM compared to controls. Patients with PPROM and high trafficking had significantly higher concentrations of the chemokine MIP-1 (CCL4) in cord blood than those with low trafficking, suggesting a mechanism for recruitment of maternal cells. CONCLUSION: This is the first demonstration of high MFCT in PPROM, with coordinate changes in inflammatory and chemotactic cytokines in fetal blood. Our observations suggest a fetal origin of labor in PPROM and indicate potential new targets for therapeutic intervention. 482 Placental histologic findings of chorion-decidual hemorrhage and inflammation in spontaneous preterm birth influence outcomes in the subsequent pregnancy David Hackney, Radhika Tirumala, Linda Salamone, Richard Miller, Philip Katzman University of Rochester School of Medicine, Obstetrics and Gynecology, Rochester, NY, University of Rochester School of Medicine, Pathology, Rochester, NY, Rochester General Hosptial, Obstetrics and Gynecology, Rochester, NY OBJECTIVE: Spontaneous preterm birth (SPTB) is a common endpoint of different underlying etiologies, including inflammation and chorion-decidual bleeding. The presumed etiology from placental histology may influence outcomes in subsequent pregnancies. STUDY DESIGN: Included subjects had: 1) a SPTB after 2004 with available placental pathology and 2) a subsequent delivery at 20 weeks EGA at our institution. Exclusion criteria were multifetal gestation, thrombophilia, anticoagulation or substance abuse. For included subjects archived placenta and membrane paraffin blocks from the index SPTB were cut, stained with Prussian Blue and evaluated by a perinatal pathologist for the presence of hemosiderin. The association between histologic findings and subsequent pregnancy outcomes were evaluated through logistic and linear regression. RESULTS: A total of 131 subjects were included, of whom 39.7% had a recurrent SPTB. The index SPTB demonstrated chorioamnionitis in 42.7%, vasculitis or funisitis in 24.4% and chorion-decidual bleeding Unadjusted and propensity score (PS)-adjusted risk ratios (95% confidence interval) of respiratory distress syndrome (RDS) and neonatal sepsis by antenatal corticosteroid (ACS) exposure and gestational age at delivery Levels of cytokines and chemokines in umbilical cord blood of normal term control patients and those with PPROM Poster Session III Doppler Assess, Fetus, Prematurity, U/S, Med-Surg-Diseases www.AJOG.org

Plasma cytokine levels and HIV-specific immune responses during acute/early HIV infection

It is believed that initial encounter between HIV and the human host triggers a complex series of events that dictate future disease course. Inter-individual differences among the host-players involved in these processes seem to early determine different rates of disease progression. Here we were aimed at studying the relationship between innate and adaptive soluble immune mediators, HIV-specific T-cell response and the course of acute infection. Methods Plasma levels of 37 cytokines were measured by Luminex technology in different groups of volunteers: 10 healthy donors (HD) and 50 HIV infected-subjects: 10 chronics, 12 aviremic controllers (EC) and 28 subjects enrolled during acute infection (AI). All HIV patients were offHAART. Frozen PBMCs from the same individuals were used to determine HIV-specific T-cell responses by IFNgamma ELISPOT. Data was compared inter- and intragroups and correlated to viral load (VL), CD4 T cell counts and both virological (VL) and immunological (CD4 count) set-points (in AI), using parametric and non-parametric statistics. Results Compared to HD, cytokines significantly elevated during acute and chronic infection included IL-1alfa, IL-10, IP-10 and TNF-alfa. Conversely, IL-12p40 and the macrophagederived chemokine (MDC) were only significantly elevated in chronics and not in AI subjects who showed similar levels to HD and even EC. Moreover, levels of IL-12p40, IL-12p70 and MDC directly correlated with CD4 T-cell count among chronics and both CD4 T-cell count and immunological set point in AI. Regarding HIV-specific T-cell response during AI, proportion of Gag-specific and Nef-specific cells significantly correlated (directly and inversely, respectively) with immunological set point. Conclusion Both early and late components of the immune system help preserve CD4 T-cell subset in HIV+ subjects: key cytokines involved in the initiation and regulation of cellular immune response and anti-Gag specificity of effector T-cells. These features should be taken into account during vaccine formulation design to boost favorable results.

Inflammatory Biomarkers Predict Airflow Obstruction After Exposure to World Trade Center Dust

The World Trade Center (WTC) collapse on September 11, 2001, produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-September 11, 2001. In a cohort of 801 never smokers with normal pre-September 11, 2001, FEV1, we correlated inflammatory biomarkers and CBC counts at monitoring entry within 6 months of September 11, 2001, with a median FEV(1) at SPE (34 months; interquartile range, 25-57). Cases of airflow obstruction had FEV(1) less than the lower limit of normal (LLN) (100 of 801; 70 of 100 had serum), whereas control subjects had FEV(1) greater than or equal to LLN (153 of 801; 124 of 153 had serum). From monitoring entry to SPE years later, FEV(1) declined 12% in cases and increased 3% in control subjects. Case subjects had elevated serum macrophage derived chemokine (MDC), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor, and interferon inducible protein-10 levels. Elevated GM-CSF and MDC increased the risk for subsequent FEV(1) less than LLN by 2.5-fold (95% CI, 1.2-5.3) and 3.0-fold (95% CI, 1.4-6.1) in a logistic model adjusted for exposure, BMI, age on September 11, 2001, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI, 27-51) and specificity of 88% (95% CI, 80-93). Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC levels soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure.