Changes In Cytokine Profile Research Articles

462P - A phase I open-label, non-randomized study of recombinant super-compound interferon (rSIFN-co) in patients with advanced solid tumours

BackgroundRecombinant super-compound interferon (rSIFN-co) is a new class of interferon derived from altering the spatial structure and configuration of the basic interferon protein. rSIFN-co displayed greater anti-tumor activity in solid tumors compared to interferon α-2b in pre-clinical studies. MethodsPatients with advanced malignancies were enrolled to determine the safety, tolerability, recommended phase II dose (RP2D), pharmacodynamics (PD) and preliminary anti-tumor activities in a 3+3 dose escalation design. rSIFN-co was dosed 3 times a week via subcutaneous injection for 21 days followed by 7 days rest. This was preceded by a lead in phase. PD studies comprised of FDG-PET, pre and post treatment changes in plasma cytokine profile and tumor repressive/ enhancing genes as well as 2’5’-oligoadenylate synthetase levels. Results39 treatment refractory patients (pts) were enrolled, 18 (46%) colorectal cancer (CRC), 11 (28%) hepatocellular carcinoma (HCC), 6 (15%) non-small cell lung cancer (NSCLC), 2 (5%) melanoma, 1 (3%) renal cell carcinoma (RCC) and 1 (3%) nasopharyngeal carcinoma (NPC). Gender M/F 25/14, median age 61.0 yrs, and ECOG 0/1/2 - 18/20/1. Patients were dosed at 4 dose levels. No dose limiting toxicities were encountered even at DL4 - 30μg (1.6×107IU) 3x/week for 21 days followed by 7 days rest. Most common drug related adverse event (drAE) includes pyrexia (92%), chills (54%), fatigue and anorexia (each 41%) and nausea (26%). Grade 3 drAEs include fatigue (8%), WBC decrease (8%), neutropenia (5%), anorexia and pyrexia and weight loss (3%). No grade 4/5 AE were reported. 2 (5.1%) had PR (2 HCC) maintained at 15.9 and 5.9 mths, 19 (48.7%) had disease control (DCR = PR+SD) of which in 6 (31.5%) DCR was >4 mths (3 HCC, 1 NSCLC and 2 CRC), and median PFS was 2.2 mths. Detailed PD data will be presented for all cohorts. ConclusionsThe RP2D of rSIFN-co was 30ug (1.6×107IU) 3x/week for 21days followed by 7 days’ rest. Anti-tumour activity seen in heavily pre-treated advanced solid tumor patients. especially in HCC. Future plans involve combinations with other immunotherapies. Clinical trial identificationNCT02387307. Legal entity responsible for the studySichuan Huiyang Life Science and Technology Corporation. FundingSichuan Huiyang Life Science and Technology Corporation. DisclosureAll authors have declared no conflicts of interest.

Associations between Monocyte and T Cell Cytokine Profiles in Autism Spectrum Disorders: Effects of Dysregulated Innate Immune Responses on Adaptive Responses to Recall Antigens in a Subset of ASD Children.

Changes in monocyte cytokine production with toll like receptor (TLR) agonists in subjects with autism spectrum disorders (ASD) were best reflected by the IL-1β/IL-10 ratios in our previous research. The IL-1β/IL-10 based subgrouping (low, normal, and high) of ASD samples revealed marked differences in microRNA expression, and mitochondrial respiration. However, it is unknown whether the IL-1β/IL-10 ratio based subgrouping is associated with changes in T cell cytokine profiles or monocyte cytokine profiles with non-TLR agonists. In ASD (n = 152) and non-ASD (n = 41) subjects, cytokine production by peripheral blood monocytes (PBMo) with TLR agonists and β-glucan, an inflammasome agonist, and T cell cytokine production by peripheral blood mononuclear cells (PBMCs) with recall antigens (Ags) (food and candida Ags) were concurrently measured. Changes in monocyte cytokine profiles were observed with β-glucan in the IL-1β/IL-10 ratio based ASD subgroups, along with changes in T cell cytokine production and ASD subgroup-specific correlations between T cell and monocyte cytokine production. Non-ASD controls revealed considerably less of such correlations. Altered innate immune responses in a subset of ASD children are not restricted to TLR pathways and correlated with changes in T cell cytokine production. Altered trained immunity may play a role in the above described changes.

Neuroinvasion of Toxocara canis- and T. cati-larvae mediates dynamic changes in brain cytokine and chemokine profile

BackgroundNeurotoxocarosis (NT) is induced by larvae of the dog or cat roundworm (Toxocara canis or T. cati) migrating and persisting in the central nervous system of paratenic hosts, including humans, and may be accompanied by severe neurological symptoms. Host- or parasite-induced immunoregulatory processes contribute to the pathogenesis, but detailed data on pathogenic mechanisms and involvement of signalling molecules during cerebral Toxocara species infections are scarce.MethodsTo elucidate alterations in immunomodulatory mediator pattern, comprehensive multiplex bead array assays profiling comprising 23 different cytokines and chemokines were performed during the course of T. canis- and T. cati-induced NT. To this end, cerebra and cerebella of experimentally infected C57Bl/6 J mice serving as paratenic host models were analysed at six different time points (days 7, 14, 28, 42, 70 and 98) post infectionem (pi).ResultsBrain-body mass ratios of T. canis and T. cati-infected mice were significantly lower than those of the uninfected control group at day 14 pi, and also at day 28 pi for T. canis-infected mice. Both infection groups showed a continuous decrease of pro-inflammatory cytokine concentrations, including TNF-α, IFN-γ, GM-CSF and IL-6, in the cerebrum over the course of infection. Additionally, T. canis but not T. cati-induced neurotoxocarosis was characterised by significantly elevated levels of anti-inflammatory IL-4 and IL-5 in the cerebrum in the acute and subacute phase of the disease. The higher neuroaffinity of T. canis led to a prominent increase of eotaxin and MIP-1α in both the cerebrum and cerebellum, while in T. cati-infected mice, these chemokines were significantly elevated only in the cerebellum.ConclusionsThe direct comparison of T. canis- and T. cati-induced NT provides valuable insights into key regulatory mechanisms of Toxocara species in paratenic hosts. The cerebral cyto-/chemokine milieu is shifted to a predominantly anti-inflammatory immune response during NT, possibly enabling both survival of the parasite and the neuroinfected paratenic host. Alteration of eotaxin and MIP-1α concentrations are congruent with the higher neuroaffinity of T. canis and species-specific tropism of T. canis to the cerebrum and T. cati to the cerebellum.

Oral Administration of Porphyromonas gingivalis, a Major Pathogen of Chronic Periodontitis, Promotes Resistance to Paclitaxel in Mouse Xenografts of Oral Squamous Cell Carcinoma.

Chemotherapy is not a first-line therapy for oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer, because most OSCC shows resistance to chemotherapeutic reagents. Inflammatory signals are suggested to be associated with chemoresistance as well as carcinogenesis in many different cancers, and thus chronic periodontitis, the most common chronic inflammatory disease of the oral cavity, could modulate responsiveness to chemotherapeutic agents used against oral cancer. This study was performed to define the role of chronic periodontitis in oral cancer progression and to determine the responsiveness of oral cancer to a chemotherapeutic reagent. First, we quantified the tumor growth rate and changes in serum cytokine profiles of mice administered Porphyromonas gingivalis, a major pathogen of chronic periodontitis. Compared with uninfected mice, the mice that were chronically administered P. gingivalis showed increased resistance to paclitaxel and a decreased tumor growth rate. In addition, P. gingivalis-treated mice exhibited higher serum levels of interleukin-6 (IL-6) than uninfected mice. Furthermore, the sensitivity of tumor xenografts to paclitaxel in mice administered P. gingivalis was dramatically increased when the mice were administered ibuprofen, an anti-inflammatory drug which supports the modulatory effect of periodontal pathogen-induced inflammation in chemoresistance.

Inflammatory model in patients with primary open angle glaucoma and diabetes

To assess the inflammatory cytokines expression in aqueous humor in diabetic primary open angle glaucoma (POAG) patients. A cross-sectional study on 87 eyes, distributed as following: 26 eyes from diabetic patients, 16 eyes with POAG and 21 eyes from diabetic POAG patients; healthy controls (24 eyes) were recruited from patients undergoing conventional cataract surgery. A volume of 100 µL of aqueous humor (AH) was collected during phacoemulsification and 21 inflammatory markers were quantified using a Luminex® cytometric bead assay: IL-1Ra, IL-1α, IL-1β, IL-5, IL-6, IL-10, IL-17, GM-CSF, IFNγ, CCL2, CCL3, CCL4, CXCL5, CXCL8, bFGF, VEGF, TNFα. Main changes in cytokine profile were analyzed and compared between groups. Data on demographics, duration of glaucoma, intraocular pressure (IOP), number of anti-glaucoma substances were recorded for correlation analysis and prediction models. Significant differences in cytokine expression between groups were detected for CXCL5 (P<0.001), CXCL8 (P=0.004), IL-1α (P<0.001), IL-2 (P<0.001), CCL4 (P=0.003), CCL5 (P<0.001) and TNFα (P=0.05). Post-hoc analysis identified IL-2 (P=0.009) and CXCL5 (P<0.001) as "separation markers" between POAG and diabetic POAG eyes. In POAG patients, the "separation markers" could highly predict the TNFα levels F(1, 16)=14.639, P<0.001, whereas in diabetic patients F(1, 24)=4.844, P=0.006 and diabetic POAG patients F(1, 19)=2.358, P=0.05 the level of prediction was inferior. Our results reveal an inflammatory model based on increased TNFα levels in POAG eyes. Simultaneous co-stimulatory molecules and additional inflammatory pathways need to be further explored in diabetic POAG cases, since the prediction model could only partially explain the increased TNFα level in this category of patients.

The supernatant of cervical carcinoma cells lines induces a decrease in phosphorylation of STAT-1 and NF-κB transcription factors associated with changes in profiles of cytokines and growth factors in macrophages derived from U937 cells.

Macrophages are presents in the tumor microenvironment and acquire different phenotypic and functional characteristics in response to microenvironmental signals. Macrophages can be differentiated into two phenotypes: M1 or pro-inflammatory (classically activated), and M2 or anti-inflammatory macrophage (alternatively activated). In response to the microenvironment, macrophages activate transcription factors as STAT1 and NF-κB-p65 for M1 macrophages or STAT3 and STAT6 for M2 macrophages; activation impacts on the profile of cytokine, chemokines and growth factors secreted by macrophages. We evaluated the effect of the supernatant of cervical-derived carcinoma cell lines HeLa, SiHa, and C-33A on the phosphorylation of transcriptional factors STAT1, NF-κB-p65, and STAT6, and their impact in the profile of secretion of cytokines and growth factors by macrophages derived from the U937 cell line. The results show that in macrophages, these supernatants induce a decrease in the phosphorylation of NF-κB-p65 and STAT1 in U937-macrophages accompanied by an increase in the secretion of IL-10, IL-6, MCP-1, and IL-8, as well as GM-CSF, G-CSF, PDGF-AA, PDGF-BB, and VEGF. Our results suggest that HeLa, SiHa, and C-33A cell lines down-regulate the activation of transcription factors characteristic of M1 macrophages (STAT1, NF-κB-p65) and induce the secretion of factors that favor tumor growth.

Cytokine profile, Treg/Th17 cell frequency changes during different posttransplantational time points in patients undergoing renal transplantation.

Renal transplantation is the best therapeutic approach for end stage renal dysfunction patients. There are direct relationships between proportions of Treg cells, Treg/Th17 cells ratio and secreted immunosuppressive cytokines with increased survival rate of the transplanted organ. The aim of this study was the measurement of Treg and Th17 cells frequency and their secreted cytokines. Ninety renal-transplanted patients were divided in three groups based on times after transplantation (1-6 month, 6-36 month, and more than 3 years). Treg and Th17 cells frequency, expression level of their transcription factors and cytokines, and their secreted cytokines level were measured in these groups. Higher expression level of Interleukin (IL)-10 and FoxP3 mRNA were observed in patients who had longer posttransplantation time. In contrast, lower mRNA expressions of IL-6, IL-17, IL-23, and TGF-β were observed in this group. Receptor γt showed no significant changes in studied groups. In addition IL-10 level was increased and IL-6, IL-17, IL-23, and TGF-β level were decreased in patients who had longer posttransplantation time. Treg cells frequency was raised in mentioned group whereas no remarkable changes were observed in Th17 cell frequency. The present study declared that in stable renal transplantation, over time, the percentage of Treg cells and Treg/Th17 ration is increased. This increase in ratio induces a change in cytokine profile, resulting in an increased immunosuppressive cytokines such as IL-10 leading to increase in the survival rate of the transplanted organ.

Depression-Induced Neuropeptide Y Secretion Promotes Prostate Cancer Growth by Recruiting Myeloid Cells.

Psychologic depression has been shown to dysregulate the immune system and promote tumor progression. The aim of this study is to investigate how psychologic depression alters the immune profiles in prostate cancer. We used a murine model of depression in Myc-CaP tumor-bearing immunocompetent FVB mice and Hi-myc mice presenting with spontaneous prostate cancer. Transwell migration and coculture assays were used to evaluate myeloid cell trafficking and cytokine profile changes evoked by Myc-CaP cells that had been treated with norepinephrine (NE), a major elevated neurotransmitter in depression. Chemoattractant, which correlated with immune cell infiltration, was screened by RNA-seq. The chemoattractant and immune cell infiltration were further confirmed using clinical samples of patients with prostate cancer with a high score of psychologic depression. Psychologic depression predominantly promoted tumor-associated macrophage (TAM) intratumor infiltrations, which resulted from spleen and circulating monocytic myeloid-derived suppressor cell mobilization. Neuropeptide Y (NPY) released from NE-treated Myc-CaP cells promotes macrophage trafficking and IL6 releasing, which activates STAT3 signaling pathway in prostate cancer cells. Clinical specimens from patients with prostate cancer with higher score of depression revealed higher CD68+ TAM infiltration and stronger NPY and IL6 expression. Depression promotes myeloid cell infiltration and increases IL6 levels by a sympathetic-NPY signal. Sympathetic-NPY inhibition may be a promising strategy for patients with prostate cancer with high score of psychologic depression.See related commentary by Mohammadpour et al., p. 2363.

Exclusive Enteral Nutrition: Clinical Effects and Changes in Mucosal Cytokine Profile in Pediatric New Inflammatory Bowel Disease.

Exclusive Enteral Nutrition (EEN) is the first-line treatment in children with Crohn’s disease (CD) for induction of remission. However, the mode of action remains conjectural. The aim of this study was to investigate whether the effect of EEN is paralleled by changes in the mucosal cytokine profiles (MCP). Twelve children with new onset inflammatory bowel disease (IBD) received induction treatment with a polymeric EEN. We assessed clinical, endoscopic and histologic scoring before and after EEN. Twelve colonic cytokines were analyzed by Polymerase Chain Reaction (PCR) in six of the IBD patients at onset and after EEN as well as in six non-IBD control children at the diagnostic colonoscopy. Twelve children completed 6 weeks of EEN, except from one child who completed 4 weeks. At the control colonoscopy, 83% were in complete clinical remission. Changes were found in the MCPs of individual patients after EEN. In particular, children with IBD showed significantly higher values of Interleukin (IL)-12β (p = 0.008) and IL-23α (p = 0.02) compared to non-IBD controls at the diagnostic colonoscopy. Furthermore, an overall change in proinflammatory cytokines was noted in the IBD-group after treatment. Further studies are warranted to understand the role of EEN in MCP.

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin.

Ricin toxin (RT) ranks at the top of the list of bioweapons of concern to civilian and military personnel alike, due to its high potential for morbidity and mortality after inhalation. In nonhuman primates, aerosolized ricin triggers severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration, and severe necrotizing bronchiolitis and alveolitis. There are currently no approved countermeasures for ricin intoxication. Here, we report the therapeutic potential of a humanized mAb against an immunodominant epitope on ricin's enzymatic A chain (RTA). Rhesus macaques that received i.v. huPB10 4 hours after a lethal dose of ricin aerosol exposure survived toxin challenge, whereas control animals succumbed to ricin intoxication within 30 hours. Antibody intervention at 12 hours resulted in the survival of 1 of 5 monkeys. Changes in proinflammatory cytokine, chemokine, and growth factor profiles in bronchial alveolar lavage fluids before and after toxin challenge successfully clustered animals by treatment group and survival, indicating a relationship between local tissue damage and experimental outcome. This study represents the first demonstration, to our knowledge, in nonhuman primates that the lethal effects of inhalational ricin exposure can be negated by a drug candidate, and it opens up a path forward for product development.

Increased interleukin-32, interleukin-1, and interferon-γ levels in serum from hepatitis B patients and in HBV-stimulated peripheral blood mononuclear cells from healthy volunteers.

Few studies showed the changes in cytokine profiles after infection by hepatitis B virus (HBV), the most common viral liver disease worldwide. This study examined the relationship between interleukin (IL)-32, IL-1, and interferon (IFN)-γ levels and HBV load. IL-32, IL-1, and IFN-γ levels in hepatitis B patients serum and HBV-stimulated PBMCs were measured by ELISA. Gene transcripts in PBMCs from hepatitis B patients and HBV-stimulated PBMCs from healthy controls were measured by real-time PCR. IL-32, IL-1, and IFN-γ protein levels in serum from hepatitis B patients were significantly higher than those in healthy volunteers (P<0.05). Hepatitis B patients showed significantly higher expression of IL-32, IL-1, and IFN-γ transcripts than healthy volunteers (P<0.05). IL-32, IL-1, and IFN-γ levels in PBMCs stimulated by different amounts of HBV were significantly higher than those in HBV-unstimulated PBMCs (P<0.05). Real-time PCR results were consistent with the ELISA results. The levels of IL-32, IL-1, and IFN-γ protein and transcripts in serum and PBMCs from hepatitis B patients were higher than those in healthy volunteers. Similarly, both were higher in PBMCs from healthy volunteers stimulated by HBV in vitro. However, the changes in cytokine levels were not proportional to the viral load.

Abstract 3133: Reprogramming of tumor-associated macrophages by a short synthetic peptide eradicates ovarian cancer

Abstract Purpose: Ovarian cancer is the deadliest gynecologic malignancy with limited treatment options and novel therapies urgently needed. Immunosuppressive microenvironment is critical for tumor progression and immune checkpoint inhibitors, which enable T-cell anticancer immunity revolutionized the outcomes in multiple cancer types. However, this approach had limited success in ovarian cancer. Our small therapeutic peptides, derived from an endogenous type 2 tumor suppressor, Pigment Epithelium-Derived Factor (PEDF), act through an alternative immune mechanism, repolarization of tumor-associated macrophages (TAMs) to the tumor-suppressive phenotype.Experimental Design: Short peptides based on the PEDF's active domain were modified for improved stability and efficacy. Two peptides (PMD-427, PMD-336) were tested in preclinical ovarian cancer models using the human chemoresistant cell line, OvCar-3, and transformed mouse cell line ID8. We also performed mechanistic analysis of the peptides' anti-tumor action, including effects on macrophages cytotoxic, cytokine secretion and migratory activity in vitro and in vivo. Results: PEDF peptide PMD-427 caused &amp;gt; 20-fold reduction in tumor burden. PMD-427 induced selective apoptosis in ovarian cancer cells but not in normal ovarian epithelium. This selectivity was based on context-specific modulation of extrinsic death cascades, Fas and FasL. More importantly, PMD-427 peptides also stimulated macrophage polarization from M2 to M1 phenotype as was evidenced by the shift in cytokine profile (decreased IL-10 and increased IL-12 expression), altered morphology (increased number of dendrite-like-processes) and other changes in M2 markers (attenuated PD-L1 expression). M2/M1 macrophage polarization was also evident by tumor immunostaining. Critically, PMD peptides ovarian cancer cell killing by macrophages as was determined in co-culture studies; this fratricidal activity was reliant on the expression of TRAIL by the macrophages and of its cognate receptor, DR5 by ovarian cancer cells, respectively. Combined with enhanced macrophage motility as observed by time-lapse micropscopy, these changes resulted in increased macrophage recruitment to the tumors and enhance killing of the cancer cells in vivo. The key role of macrophages in the anti-cancer effects of PMD peptides was confirmed by depletion of macrophages in ovarian tumor bearing mice using clodronate liposomes. Conclusions: We have generated a first-in-class multi-targeted peptide drug, which promotes macrophage polarization that results in eradication of ovarian tumors in mice. Citation Format: Reshma Bhowmick, Elena Vinokour, Michael Paul Plebanek, Marisol Villanueva, Victor Shifrin, Jack Henkin, Ignacio Melgar-Asensio, James Petrik, Raghu Kallurie, Olga V. Volpert. Reprogramming of tumor-associated macrophages by a short synthetic peptide eradicates ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3133.

Changes in cytokine levels after prolonged and repeated moderate intensity exercise in middle-aged men and women

Previous studies have shown that exercise-induced changes in cytokine profiles depend on exercise duration and intensity. Studies are generally limited to a single day, and insight into the time course during multiple days of exercise is lacking. Therefore, this study assessed cytokine responses during multiple days of moderate intensity exercise in men and women. Fifty males (58.9 ± 9.9 years) and fifty females (50.9 ± 11.2 years) were monitored on 4 consecutive days at which they walked on average ~9 h/d at a self-determined pace. Blood samples were collected 1 or 2 days prior to the start of the exercise (baseline) and every walking day immediately post-exercise. Blood samples were analyzed for IL-6, IL-8, IL-10, IL-1β, and TNF-α concentrations. All cytokine concentrations increased from baseline to post-exercise at day 1 (P < .001). Thereafter, concentrations decreased from day 1 to day 2 (P < .01), remaining rather stable during the next days. IL-1β and TNF-α were higher in men at baseline and during all days. In conclusion, exercise-induced cytokine increases attenuated on subsequent days, although daily workload remained constant. Men and women showed different baseline levels but similar exercise responses. These results suggest that individuals adapt rapidly to this type of repeated exercise.

74 - Expanding mesenchymal stem cells with platelet lysate vs FBS increases bioreactor efficiency but alters cytokine prolife

Bone-marrow derived mesenchymal stem cells (BM-MSCs) are a leading cell product candidate for the treatment of multiple inflammatory, degenerative, and chronic diseases. However, conventional culture methods (with T175 cm2 culture flasks) lack practicable scalability. The production of a lot containing 500 million clinical-grade BM-MSCs is a labor-intensive process that requires a highly-coordinated effort of four well-trained technical staff members. Therefore, bioreactors have been developed as a cost effective and scalable method of producing BM-MSCs. We have validated a Quantum bioreactor (Terumo) method using passage 1, human BM-MSCs isolated from 4 different donors to efficiently produce potent clinical-grade products using both 5% human Platelet Lysate (hPL) and 20% Fetal Bovine Serum (FBS) containing medias. Our harvested products were characterized by proliferation analysis, daily cell lactate production, colony forming unit (CFU) analysis, cell surface protein expression, and cytokine profile. Head to head comparison of hPL and FBS cultured products showed a 5.1 ± 1.46-fold, (P < 0.05) increased efficiency of bioreactor expansion of BM-MSC in hPL media, producing 7.68 × 108 ± 1.25 vs 2.21 × 108 ± 0.92 cells with a seeding of 1.0–2.5 × 107 cells, respectively (P < 0.05). Furthermore, BM-MSCs formed CFUs and had positive expression of CD105, CD90, CD44, and CD75 and negative expression of CD45, CD31, and CD34. Interestingly, cytokine analysis of 80 cytokine targets revealed differences in the BM-MSC secretomes produced in hPL vs FBS media. Expansion in hPL upregulated RANTES (+8.1 ± 1.3-fold, P < 0.05) and downregulated IL-6 (−2.13 ± 0.72-fold, P < 0.05), SDF-1 (−1.62 ± 0.18-fold, P < 0.001), VEGF (−1.57 ± 0.24-fold, P < 0.01), and Angiogenin (−1.6 ± 0.11-fold, P < 0.001), significantly. Additionally, consistent upregulations of IL-8 (+2.29 ± 0.69-fold) and MCP-3 (+6.76 ± 3.6-fold) was documented in hPL-produced BM-MSCs. Together, these results confirm the superiority of hPL expansion of BM-MSCs in the Quantum bioreactor but reveals an alteration to the cytokine prolife. To date, many clinical trials have been done with BM-MSC produced in FBS containing media. However, due to concerns involving the use of animal-derived products, GMP-facilities are beginning to switch to hPL containing media. Our results show that this switch is feasible, however changes in BM-MSC cytokine profile should be taken into consideration depending upon the clinical application.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Rotavirus intestinal infection induces an oral mucosa cytokine response.

IntroductionSalivary glands are known immune effector sites and considered to be part of the whole mucosal immune system. The aim of the present study was to assess the salivary immune response to rotavirus (RV) infection through the analysis of the cytokine immune profile in saliva.Material and methodsA prospective comparative study of serial saliva samples from 27 RV-infected patients (sampled upon admission to the hospital during acute phase and at convalescence—i.e. at least three months after recovery) and 36 healthy controls was performed. Concentrations of 11 salivary cytokines (IFN-γ, IFN-α2, IL-1β, IL-6, IL-8, IL-10, IL-15, IL12p70, TNF-α, IFN-λ1, IL-22) were determined. Cytokine levels were compared between healthy controls acute infection and convalescence. The correlation between clinical data and salivary cytokine profile in infected children was assessed.ResultsThe salivary cytokine profile changes significantly in response to acute RV infection. In RV-infected patients, IL-22 levels were increased in the acute phase with respect to convalescence (P-value < 0.001). Comparisons between infected and control group showed significant differences in salivary IFN-α2, IL-1β, IL-6, IL-8, IL-10 and IL-22. Although acute-phase levels of IL-12, IL-10, IL-6 and IFN-γ showed nominal association with Vesikari’s severity, this trend did not reach statistical significance after multiple test adjustment.ConclusionsRV infection induces a host salivary immune response, indicating that immune mucosal response to RV infection is not confined to the intestinal mucosa. Our data point to a whole mucosal implication in the RV infection as a result of the integrative mucosal immune response, and suggest the salivary gland as effector site for RV infection.

Alterations in plasma cytokine levels in chinese children with autism spectrum disorder.

Alteration of immune system function is an important risk factor for autism spectrum disorder (ASD). Here we found that the levels of cytokines, including Eotaxin, TGF-β1 and TNF-α, are elevated in Chinese children with ASD, as compared to typically developing children. The change in TGF-β1 level was most prominent in boys, while that of Eotaxin was more significant in girls. These results provide evidence for changes in cytokine profile in Chinese children with ASD.

Mixed and inhomogeneous expression profile of Th1/Th2 related cytokines detected by cytometric bead array in the saliva of patients with oral lichen planus

The aim of this study was to measure T helper (Th) 1/Th2-related cytokine expression in saliva from patients with oral lichen planus (OLP), compared with healthy controls (HC group) and controls with recurrent aphthous ulcers (RAU group). Saliva was collected from 41 patients with OLP, 14 HCs, and 14 controls with RAU for Th1/Th2-related cytokines analysis with cytometric bead array. Disease activity in OLP was recorded by reticulation/keratosis, erythema, and ulceration scores. Interleukin (IL)-6, IL-10, interferon-γ (IFN-γ), and IFN-γ/IL-4 in saliva were significantly higher in the OLP group than in the HC group. A positive and significant correlation among IL-6, IL-10, and reticulation/keratosis, erythema, and ulceration scores in the OLP group was revealed. Significantly increased IL-4, IL-5, IL-6, IL-10, tumor necrosis factor-α and IFN-γ/IL-4 were found in the RAU group. Salivary cytokine profiles analyzed by cytometric bead array may provide a convenient research approach to OLP. Data indicated complicated Th1/Th2-related cytokine profile changes, rather than simple dominance model, in OLP. IL-10 and especially IL-6 may provide a surrogate endpoint for monitoring OLP.

Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma

AbstractDuvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)–δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-δ–specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell–autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657.

Neuromodulation in Inflammatory Skin Disease.

Inflammatory skin diseases are difficult to treat because of a lack of available treatment options for severe disease. However, recent advances have shown that vagus nerve stimulation can be used to decrease inflammation and reduce disease severity in rheumatoid arthritis and inflammatory bowel disease. Changes in cytokine profiles observed in these studies are similar to those seen with use of biologics in inflammatory skin disease, suggesting that they act along similar pathways to disrupt chronic inflammation and treat inflammatory disease. This commentary explores the existing evidence demonstrating the efficacy of neuromodulation in inflammatory disease, and outlines reasons why these findings could translate to the dermatology setting to treat inflammatory skin disease.