IL-17A Receptor Research Articles

Locally Targeting the IL-17/IL-17RA Axis Reduced Tumor Growth in a Murine B16F10 Melanoma Model.

Interleukin (IL)-17 and the cells that produce it within the tumor microenvironment appear to promote tumor development and are associated with survival in cancer patients. Here we investigated the role of the IL-17/IL-17 receptor A (IL-17RA) axis in regulating melanoma progression and evaluated the therapeutic potential of blocking the IL-17/IL-17RA pathway. First, recombinant mouse IL-17 (γmIL-17) treatment significantly increased proliferation of mouse B16F10 cells and human A375 and A2058 cells. Silencing IL-17RA by small hairpin RNA (shRNA) in B16F10 cells reduced the γmIL-17-elicited cell proliferation, migration, and invasion, and significantly reduced vascular endothelial growth factor and matrix metalloproteinase production. Remarkably, knockdown of IL-17RA led to a significantly decreased capability of B16F10 cells to form tumors in vivo, similar to that in IL-17-deficient mice. Finally, local application of an adenovirus delivering a shRNA against IL-17RA mRNA not only significantly suppressed tumor development, but also enhanced antitumor immunity by increasing the interferon γ-expressing T cells and not T regulatory cells. Our results highlight the critical role of the IL-17/IL-17RA pathway in tumor progression and imply that targeting IL-17RA represents a promising therapeutic strategy.

Involvement of interleukin-31 receptor A in morphine-induced itching and antinociception in mice.

Morphine is an effective analgesic for the treatment of severe pain, but it can cause itching in patients. In the present study, we examined the possible involvement of interleukin-31 (IL-31) receptor A (IL-31RA) on the morphine-induced itching and antinociception in mice. Long-lasting scratching (LLS) and short-lasting scratching (SLS) were estimated as an indicator of itching and nonspecific behaviour, respectively, and antinociception was evaluated using a hot-plate test in mice. Morphine (5mg/kg, s.c.) induced multiple episodes of SLS, few episodes of LLS, and antinociception in naive mice, with a close correlation observed between SLS or LLS counts and antinociception. In IL-31RA-deficient (IL-31RA-/- ) mice, morphine (5mg/kg, s.c.)-induced LLS but not SLS was completely abolished, while antinociception was partially suppressed with 2.5 and 5mg/kg but not 10mg/kg, s.c. of morphine administration. Interestingly, intracerebroventricular (i.c.v.) administration of morphine (10μg/mouse) significantly increased SLS but not LLS, and this effect was higher in IL-31RA-/- mice than that in wild-type mice. Furthermore, following i.c.v. administration of morphine (10μg/mouse), the antinociceptive effect was also significantly higher in IL-31RA-/- mice than that in wild-type mice. Taken together, the present findings suggest that IL-31RA may play a significant role, perhaps in the sensory neurons and/or spinal cord rather than in the brain, in the modulation of morphine-induced itching and antinociception. Here, we demonstrate a possible common mediator of itching and antinociception of morphine, interleukin-31 (IL-31) receptor A (IL-31RA). IL-31RA may be a noteworthy target for considering the novel mechanism of itch and pain signalling affected by morphine.

Tc17/IL-17A Up-Regulated the Expression of MMP-9 via NF-κB Pathway in Nasal Epithelial Cells of Patients With Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease of the upper airways involving nasal cavity and sinus. Deriving both from its clinical complexity with protean clinical manifestations as well its pathogenetic heterogeneity, the molecular mechanisms contributing to the pathogenesis of CRS remain unclear, and attract a wide interest in the field. Current evidences indicate that IL-17A is highly expressed in chronic rhinosinusitis with nasal polyps (CRSwNP). However, its pathogenetic role in regulation of tissue remodeling of CRSwNP remains unknown. The present study aimed to investigate the cellular origins and functions of IL-17A cytokine in CRSwNP, and further determined whether IL-17A could affect the expression of metalloproteinases (MMPs), the remodeling factors of CRSwNP. The results showed that the expression of IL-17A was upregulated in nasal tissues of patients with CRSwNP compared to those with chronic rhinosinusitis without nasal polyps (CRSsNP) and controls. CD8+ cytotoxic T lymphocytes (Tc) were major IL-17A producers in nasal tissues of CRSwNP. Interleukin (IL)-17-producing CD8+ T cells (Tc17) was significantly higher in nasal tissues of CRSwNP than CRSsNP and controls. Nonetheless, no difference was observed among the IL-17A in peripheral blood lymphocytes of these three groups. Moreover, in the same patients, IL-17A expression was negligible in lymphocytes of peripheral blood when compared with nasal tissues. Increased gene and protein expression of MMP-7 and MMP-9 in patients with CRSwNP compared with controls were observed. In CRSwNP samples, IL-17A receptor (IL-17AR) co-localized with MMP-9 and they were mainly expressed in the epithelial cells. MMP-9 expression was up-regulated both in Primary human nasal epithelial cells (PHNECs) and a nasal epithelial cell line (RPMI 2650) by IL-17A treatment, and diminished by anti-IL-17AR treatment. Furthermore, IL-17A promoted the expression of MMP-9 by activating the NF-κB signal pathway. Thus, our results have revealed a crucial role of IL-17A and Tc cells on pathogenesis and tissue remodeling of CRSwNP.

Role of IL‐17A receptor blocking in melanocyte survival: A strategic intervention against vitiligo

Cytokines regulate immune response and inflammation and play an important role in depigmentation process of an autoimmune disease, vitiligo. We sought to determine how inflammatory cytokines influence the progression of vitiligo, and based on that, we develop a logical therapeutic intervention using primary melanocyte culture. Melanocytes were cultured and exposed to IL-17A, IL-1β, IFN-γ and TGF-β for 4days. Melanocytes proliferation, tyrosinase assay and melanin content were measured. Real-Time PCR was used to analyse mRNA expression of genes specific for melanocytes growth and pigmentation. Anti-IL-17A receptor antibody was used to block IL-17A receptors expressed on melanocytes. Protein expression of MITF and TYR was assessed by immunofluorescence and Western blotting. A gradual decline in the melanocyte population, melanin content and tyrosinase activity was observed after different cytokine treatment. The expression of MITF and its downstream genes after blocking with anti-IL-17RA, an increased melanin content, increased expression of TYR, MITF along with its downstream genes, and cell proliferation was observed.

T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis.

T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αβT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αβT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN αβT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αβTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null αβT cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis.

Electrochemical immunosensor for IL-13 Receptor α2 determination and discrimination of metastatic colon cancer cells

This work describes the first electrochemical immunosensor reported for the determination of IL-13 receptor Rα2 (IL-13Rα2), an emerging relevant biomarker in metastatic colon cancer. The approach involves the formation of sandwich immunocomplexes using specific capture (CAb) and biotinylated detector antibodies (BDAb) further labeled with an streptavidin-horseradish peroxidase (Strep-HRP) polymer, onto carboxylic acid-modified magnetic microbeads (HOOC-MBs). Amperometric detection at disposable carbon screen-printed electrodes (SPCEs) using the (H2O2)/hydroquinone (HQ) system was employed to monitor the affinity reactions. The developed immunosensor exhibits a linear calibration plot over the 3.9–100 ng mL−1 concentration range, a LOD of 1.2 ng mL−1 and excellent selectivity against other non-target proteins. The amperometric immunosensor was applied successfully to quantify for the first time the IL-13Rα2 expression in raw lysates of colon cancer cells and to discriminate the metastatic potential of intact cells through recognition of this target extracellular receptor. In comparison with the commercial Enzyme-Linked ImmunoSorbent Assay (ELISA) kit involving the same immunoreagents, the immunosensor provides a similar LOD in a half-time for the assay.

Blocking IL-13 receptor α2 using polyethylene glycol functionalized superparamagnetic iron oxide nanocarriers to inhibit proliferation and mediate apoptosis in NSCLC cells

Blocking IL-13 receptor α2 using polyethylene glycol functionalized superparamagnetic iron oxide nanocarriers to inhibit proliferation and mediate apoptosis in NSCLC cells

A bi-specific inhibitor targeting IL-17A and MMP-9 reduces invasion and motility in MDA-MB-231 cells

The cytokine IL-17A is associated with the progression of various cancers, but little is known about the molecular cross-talk between IL-17A and other tumor-promoting factors. Previous studies have shown that the IL-17A-mediated invasion of breast cancer cells can be inhibited by selective antagonists of the matrix metalloproteinase 9 (MMP-9), suggesting that the cross-talk between IL-17A and MMP-9 may promote cancer invasiveness and metastasis. Here, we present a novel strategy for developing cancer therapeutics, based on the simultaneous binding and inhibition of both IL-17A and MMP-9. To this end, we use a bi-specific heterodimeric fusion protein, comprising a natural inhibitor of MMPs (N-TIMP2) fused with an engineered extracellular domain (V3) of the IL-17A receptor. We show that, as compared with the mono-specific inhibitors of IL-17A (V3) and MMP-9 (N-TIMP2), the engineered bi-specific fusion protein inhibits both MMP-9 activation and IL-17A-induced cytokine secretion from fibroblasts and exhibits a synergistic inhibition of both the migration and invasion of breast cancer cells. Our findings demonstrate, for the first time, that dual targeting of inflammatory (IL-17A) and extracellular matrix remodeling (MMP) pathways can potentially be used as a novel therapeutic approach against cancer. Moreover, the platform developed here for generating the bi-specific IL-17A/MMP-9 inhibitor can be utilized for generating bi-specific inhibitors for other cytokines and MMPs.

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity.

Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.

761 Topically-delivered gene suppressing nanocontruct targets IL-17RA for psoriasis

Activated interleukin (IL)-23/Th17 signaling is critical for psoriasis pathogenesis, and systemic IL-17 inhibitors are highly effective therapy. However, most patients have mild to moderate disease and no targeted topical therapeutic option. We developed a topically-delivered gene regulating nanoconstruct, comprised of antisense DNA or siRNA in a dense spherical configuration. These spherical nucleic acids or SNAs penetrate the skin barrier to knock down cutaneous gene targets. We generated anti-human and anti-mouse liposomal DNA SNAs targeting the IL-17A receptor (ILRA) and tested their efficacy in reducing IL17RA and improving markers of psoriasis in human 3D and imiquimod-induced mouse models of psoriasis. SNAs reduced human keratinocyte IL-17RA expression by 83% versus scrambled SNAs (p<0.001). 100nM IL17RA SNAs, applied to the surface of cytokine-generated psoriatic 3D rafts every other day from day 7 to 13, inhibited keratinocyte proliferation, reduced IL17RA mRNA (by 67%; p<0.01) and IL-17-induced genes (e.g., DEFβ4, TNF, and PI3 by 64%, 73%, and 71%, respectively; all p<0.001), and improved differentiation (e.g., increased LOR by 2.7-fold; p<0.05) compared to scrambled SNA and vehicle controls. By day 6 in the imiquimod-induced psoriasis-like mouse, topical IL17RA SNA (50μM) reduced psoriasis severity (modified PASI) by 75% (p<0.001) and epidermal thickness (histology) by 52% (p<0.001) compared to controls. IL17RA SNA decreased IL17RA, DEF4, and S100A7 mRNA by 57%, 82%, and 55%, respectively compared to the scrambled SNA control (p<0.01). These data suggest that targeted suppression of IL17RA, or both IL-17R and TNFα using a bispecific SNA, is a promising new treatment strategy for mild to moderate psoriasis.

Role of IL-13Rα2 in modulating IL-13-induced MUC5AC and ciliary changes in healthy and CRSwNP mucosa.

The IL-13 receptor α2 (IL-13Rα2) is a receptor for IL-13 which has conflicting roles in mediating IL-13 responses in the lower airway, with little known about its impact on upper airway diseases. We sought to investigate the expression of IL-13 receptors, IL-13Rα1 and IL-13Rα2, in chronically inflamed nasal epithelium, and explore IL-13-induced signaling pathways in an invitro model of human nasal epithelial cells (hNECs). The protein and mRNA expression levels of IL-13 and its receptors in nasal biopsies of patients with nasal polyps (NP) and healthy controls were evaluated. We investigated goblet cell stimulation with mucus hypersecretion induced by IL-13 (10ng/mL, 72hours) treatment in hNECs using a pseudostratified epithelium in air-liquid interface (ALI) culture. There were significant increases in IL-13, IL-13Rα1, and IL-13Rα2 mRNA and protein levels in NP epithelium with healthy controls as baseline. MUC5AC mRNA positively correlated with IL-13Rα2 (r=.5886, P=.002) but not with IL-13Rα1 in primary hNECs. IL-13 treatment resulted in a significant increase in mRNA and protein levels of IL-13Rα2 only in hNECs. IL-13 treatment induced an activation of extracellular signal-regulated kinases (ERK)1/2 and an upregulation of C-JUN, where the IL-13-induced effects on hNECs could be attenuated by ERK1/2 inhibitor (50μmol/L) or dexamethasone (10-4 -10-7 mol/L) treatment. IL-13Rα2 has a potential role in IL-13-induced MUC5AC and ciliary changes through ERK1/2 signal pathway in the nasal epithelium. IL-13Rα2 may contribute to airway inflammation and aberrant remodeling which are the main pathological features of CRSwNP.

Interleukin-17A participates in podocyte injury by inducing IL-1β secretion through ROS-NLRP3 inflammasome-caspase-1 pathway.

Studies show that the Th17/IL-17A axis plays an important role in the pathogenesis of kidney diseases. Previously, we also showed that IL-17A may play a role in the pathogenesis of primary nephrotic syndrome; however, the underlying mechanism(s) is unclear. The aim of this study was to explore the molecular mechanism of IL-17A-inducing podocyte injury invitro. In this study, the NLRP3 inflammasome activation and the morphology of podocytes were detected by Western blot and immunofluorescence. The results showed that podocytes persistently expressed IL-17A receptor and that NLRP3 inflammasome in these cells was activated upon exposure to IL-17A. Also, activity of caspase-1 and secretion of IL-1β increased in the presence of IL-17A. In addition, IL-17A disrupted podocyte morphology by decreasing expression of podocin and increasing expression of desmin. Blockade of intracellular ROS or inhibition of caspase-1 prevented activation of the NLRP3 inflammasome, thereby restoring podocyte morphology. Taken together, the results suggest that IL-17A induces podocyte injury by activating the NLRP3 inflammasome and IL-1β secretion and contributes to disruption of the kidney's filtration system.

TAOK1 negatively regulates IL-17-mediated signaling and inflammation.

Interleukin 17 (IL-17) is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases. However, the regulation of its signaling transduction has not been well described. In this study, we report that thousand and one kinase 1 (TAOK1) functions as a negative regulator of IL-17-mediated signal transduction and inflammation. TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-κB. We further demonstrate that TAOK1 interacts with IL-17 receptor A (IL-17RA) independent of its kinase activity, and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1 (nuclear factor activator 1, also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2) complex. Consistent with this, TAOK1 deficiency exacerbates colitis in the 2,4,6-trinitrobenzenesulfonic acid)-induced experimental model of inflammatory bowel disease, likely by its promotion of the IL-17-mediated signaling pathway. TAOK1 expression is decreased in the colons of ulcerative colitis patients. In conclusion, these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders.

Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis.

Background & AimsAtrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy.MethodsA mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia.ResultsIncreased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis.ConclusionsThese data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer.

The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis

Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a previously unappreciated role for cardiac fibroblasts in facilitating both Ly6Chi and Ly6Clo monocyte-to-macrophage differentiation, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation. We demonstrated an inverse correlation of cardiac IL-17A and efferocytic receptor expression in human heart failure. During the resolution of inflammation, Ly6Clo monocyte-to-macrophage differentiation is restored as IL-17A signaling through cardiac fibroblast subsides. Ly6Clo monocyte-derived macrophages exhibit robust MHC class II-associated antigen presentation but are incapable of engulfing debris. We propose that MHCII+ Ly6Clo monocyte-derived macrophages may prevent fibrosis and heart failure.

Analysis of the cancer genome atlas (TCGA) database identifies an inverse relationship between interleukin-13 receptor \u03b11 and \u03b12 gene expression and poor prognosis and drug resistance in subjects with glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. A variety of targeted agents are being tested in the clinic including cancer vaccines, immunotoxins, antibodies and T cell immunotherapy for GBM. We have previously reported that IL-13 receptor subunits α1 and α2 of IL-13R complex are overexpressed in GBM. We are investigating the significance of IL-13Rα1 and α2 expression in GBM tumors. In order to elucidate a possible relationship between IL-13Rα1 and α2 expression with severity and prognoses of subjects with GBM, we analyzed gene expression (by microarray) and clinical data available at the public The Cancer Genome Atlas (TCGA) database (Currently known as Global Data Commons). More than 40% of GBM samples were highly positive for IL-13Rα2 mRNA (Log2 ≥ 2) while only less than 16% samples were highly positive for IL-13Rα1 mRNA. Subjects with high IL-13Rα1 and α2 mRNA expressing tumors were associated with a significantly lower survival rate irrespective of their treatment compared to subjects with IL-13Rα1 and α2 mRNA negative tumors. We further observed that IL-13Rα2 gene expression is associated with GBM resistance to temozolomide (TMZ) chemotherapy. The expression of IL-13Rα2 gene did not seem to correlate with the expression of genes for other chains involved in the formation of IL-13R complex (IL-13Rα1 or IL-4Rα) in GBM. However, a positive correlation was observed between IL-4Rα and IL-13Rα1 gene expression. The microarray data of IL-13Rα2 gene expression was verified by RNA-Seq data. In depth analysis of TCGA data revealed that immunosuppressive genes (such as FMOD, CCL2, OSM, etc.) were highly expressed in IL-13Rα2 positive tumors, but not in IL-13Rα2 negative tumors. These results indicate a direct correlation between high level of IL-13R mRNA expression and poor patient prognosis and that immunosuppressive genes associated with IL-13Rα2 may play a role in tumor progression. These findings have important implications in understanding the role of IL-13R in the pathogenesis of GBM and potentially other cancers.

Th17 pathway in recent-onset autoimmune diabetes

AimsEvaluate the participation of IL-17 pathway in T1D pathogenesis. T helper 17 cells are potent, highly inflammatory cells that produce interleukin 17A (IL-17A), considered a mediator of various immune disorders. However, their role in Type 1 diabetes (T1D) pathogenesis in humans is not totally elucidated. MethodsThe expression of IL-17 Receptor A (IL-17RA) in peripheral T lymphocytes and IL-17A serum levels in recent-onset patients with T1D were compared with healthy controls. IL-17A gene variants were evaluated in a greater cohort. ResultsPatients with recent-onset T1D (less than 6 months of diagnosis) exhibited lower expression of IL-17RA in CD3+ T (% of cells = 31.3% × 43.6%; p = .041) and CD4+ T cells (11.1% × 25.2%; p = .0019) and lower number of IL-17RA in CD4+ T cells (MFI = 1.16 × 4.56; p = .03) than controls. IL-17RA expression in CD8+ T cells and IL-17A serum levels were similar in both groups. The coding regions and boundary intron sequences of IL17A were sequenced. Seventeen allelic variants, including three novel variants in exon 3 (3′UTR n) were identified, but no one was associated with T1D susceptibility, as well as the resulting haplotypes and diplotypes. The expression of IL-17RA was not correlated with metabolic variables (glucose and HbA1c levels) or pancreatic autoantibodies titers. ConclusionsThe lower expression of IL-17RA in CD3+ and CD4+ T cells suggests a reduced effect of IL-17A in immune response of recent-onset T1D patients, at least at peripheral tissues. IL-17A allelic variants were not related with T1D susceptibility.

Newer treatments of psoriasis regarding IL-23 inhibitors, phosphodiesterase 4 inhibitors, and Janus kinase inhibitors.

The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23). Phosphodiesterase inhibitors exert an anti-inflammatory action and their most common group is the PDE4 family. PDE4 inhibits cAMP, which reduces the inflammatory response of the pathway of Th helper lymphocytes, Th17, and type 1 interferon which modulates the production of anti-inflammatory cytokines such as IL-10 interleukins. The Janus kinase (JAK) signaling pathway plays an important role in the immunopathogenesis of psoriasis. Tofacitinib suppresses the expression of IL-23, IL-17A, IL-17F, and IL-22 receptors during the stimulation of lymphocytes. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 kinases and the JAK-STAT signaling pathway. This article is a review of the aforementioned drugs as described in the latest available literature.

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma.

T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) Tcell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR Tcells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory Tcells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR Tcells improved anti-tumor activity and Tcell persistence as compared to first-generation IL13ζ-CAR CD8+ Tcells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR Tcell anti-tumor activity invivo. Furthermore, we found that local intracranial delivery of CAR Tcells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR Tcell therapy for the treatment of brain tumors.

Activation of IL-17 receptor leads to increased oxidative inflammation in peripheral monocytes of autistic children

Millions of children are affected by different neurodevelopmental disorders, out of which autism spectrum disorder (ASD) poses a major hurdle to normal life style due to associated behavioral abnormalities. Several studies have shown an increased expression/release of Th17 related cytokine, IL-17A in ASD. IL-17A may enhance neuroinflammation via its IL-17A receptor, i.e. IL-17RA expressed in immune cells (such as monocytes) of autistic children. Increased oxidative stress has been implicated in a number of neuropsychiatric disorders including ASD. However, whether IL-17A/IL-17RA signaling contributes to oxidative inflammation in monocytes of autistic children has not been explored previously. With this background, we performed this study in peripheral monocytes of ASD patients and age-matched typically developing children. Our study shows that ASD individuals have increased IL-17RA expression in monocytes which is associated with increased nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway and inducible nitric oxide synthase (iNOS)/nitrotyrosine expression as compared to typically developing children. Moreover, in vitro activation of IL-17 receptor by IL-17A in monocytes isolated from ASD individuals leads to enhanced iNOS expression via NFκB pathway. IL-17RA antibody treatment in vitro reversed IL-17A-induced increase in NFκB and iNOS/nitrotyrosine expression in monocytes isolated from ASD subjects. These data connect increased IL-17A/IL-17RA signaling in ASD patients with enhanced oxidative inflammation in monocytes. Therefore, IL-17 receptor signaling in monocytes may potentiate the effects of IL-17A released by other immune cells and may aggravate neuroinflammation in ASD. Our study further suggests that blockade of IL-17A/IL-17 receptor signaling may be beneficial in the children with ASD.