Anti-IL-4Rα monoclonal antibody (CM310) in patients with chronic rhinosinusitis with nasal polyps (CROWNS-2): Rationale and design of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease that affects a large proportion of the global population. The treatment of CRSwNP, especially eosinophilic CRSwNP (ECRSwNP), has always been of great obstacle. Our previous phase 2 trial showed that CM310, a monoclonal antibody that targets interleukin-4 receptor alpha, was both safe and effective in reducing the size of nasal polyps, improving symptom scores, and increasing the quality of life for those with severe ECRSwNP. Objective: This phase 3 trial aims to evaluate the efficacy, safety, pharmacokinetic, pharmacodynamic, and immunogenicity of CM310 in participants with CRSwNP. Result: The CROWNS-2 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial. The study consisted of a screening/run-in period (up to 4 weeks), a treatment period (24-week double-blind treatment period plus 28-week maintenance period), and a safety follow-up period (8 weeks). The study planned to enroll 180 participants with CRSwNP (at least 60% of ECRSwNP) to receive CM310 300 mg/placebo every 2 weeks (Q2W) subcutaneously for a total of 12 doses in double-blind treatment period and 300 mg CM310 Q2W subcutaneously for a total of 14 doses in maintenance period. Enrolled participants continued to use mometasone furoate nasal spray throughout the study. The primary endpoints are a change from baseline in nasal polyp score and nasal congestion score at week 24 between CM310 and placebo in both ECRSwNP and CRSwNP. Conclusion: The CROWNS-2 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical study to evaluate the efficacy and safety of CM310 in patients with CRSwNP. Trial registration: NCT05436275.

Association Between Smell Loss, Disease Burden, and Dupilumab Efficacy in Chronic Rhinosinusitis with Nasal Polyps.

OBJECTIVE: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss. METHODS: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0-8), nasal congestion/obstruction (NC, 0-3), Lund-Mackay CT-scan score (LMK-CT, 0-24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0-110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0-3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks. RESULTS: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS -1.90 (-2.56, -1.25) and -1.95 (-2.20, -1.70) in the moderate and severe baseline LoS subgroups, respectively; NC -.35 (-.64, -.06) and -1.00 (-1.13, -.87); LMK-CT -6.30 (-7.88, -4.72) and -6.22 (-6.82, -5.63); RS-VAS -1.18 (-2.20, -.16) and -3.47 (-3.90, -3.03); and SNOT-22 -7.52 (-14.55, -.48) and -21.72 (-24.63, -18.82); all nominal P < .05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS. CONCLUSION: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss.

Paradoxical Psoriasis.

Cytokine blocking therapies have revolutionized the management of psoriasis and atopic dermatitis but can lead to the development of paradoxic psoriasis (PP). Patients treated with biologics should be closely monitored for the development of PP and other paradoxical eruptions (including inflammatory joint disease, inflammatory bowel disease, eczematous eruptions, lupus like eruptions, sarcoidal eruptions, and others) and occasionally the development of cutaneous T-cell lymphoma. Further understanding the immunologic mechanism of these processes will ultimately drive our understanding of and ability to predict and manage PPs.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial.

Background: There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. Methods: In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300 mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Findings: Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300 mg QW (n = 31), stapokibart 600-300 mg Q2W (n = 30), or placebo QW (n = 31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were -1.0 (-2.3, 0.2) in stapokibart Q2W group (p = 0.065) and -0.2 (-1.5, 1.0) in stapokibart QW group (p = 0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference -12.9%, 95% CI -25.3%, -0.4%, p = 0.043), as well as AM iTNSS over 2 weeks (LS mean difference -17.4%, 95% CI -31.0%, -3.8%, p = 0.013) and 4 weeks (LS mean difference -15.4%, 95% CI -29.0%, -1.9%, p = 0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference -0.4, 95% CI -0.7, -0.1, p = 0.014) and 4-week (LS mean difference -0.4, 95% CI -0.7, -0.04, p = 0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. Interpretation: In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Funding: Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

Efficacy and safety of CM310 in severe eosinophilic chronic rhinosinusitis with nasal polyps (CROWNS-1): a multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial.

Background: Severe eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remains the most relapsed subtype of uncontrolled CRSwNP. CM310, a humanised anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits IL-4 and IL-13 signaling which underlying eosinophilic inflammation. This study aims to evaluate the efficacy and safety of CM310 in patients with severe ECRSwNP. Methods: A multicentre, randomised, double-blind, and placebo-controlled phase 2 clinical trial was conducted. 56 eligible adult patients with severe ECRSwNP were randomised 1:1 to receive subcutaneously either CM310 (300 mg) or placebo every 2 weeks under the background therapy of mometasone furoate nasal spray (MFNS) for 16 weeks, with 8 weeks of follow-up. Coprimary endpoints included the changes from baseline in nasal polyp score (NPS) and nasal congestion score (NCS) at week 16. Key secondary endpoints included sinus Lund-Mackay CT score, change in sinus volume occupied by disease, University of Pennsylvania Smell Identification Test score, 22-item Sino-nasal Outcome Test score, and total symptom score. Safety, pharmacodynamics, and changes in type 2 inflammation biomarkers were assessed. This study is registered with ClinicalTrials.gov, NCT04805398. Findings: Between April 6, 2021, and March 18, 2022, 27 patients respectively in both the CM310 and placebo groups completed the study. Findings suggested that CM310 improved the coprimary efficacy endpoints of decreasing nasal polyp size and alleviating nasal congestion compared with the placebo. Least squares (LS) mean differences (CM310 vs placebo) of change from baseline in NPS and NCS at week 16 were -2.1 (95% CI -2.9, -1.4; p < 0.0001) and -0.9 (95% CI -1.4, -0.5; p < 0.0001), respectively. Sinus CT scan revealed that Lund-Mackay CT score (LS mean difference [95% CI] -7.6, [-9.4, -5.8]; p < 0.0001) and sinus volume occupied by disease (LS mean difference [95% CI] -37%, [-47%, -28%]; p < 0.0001) were significantly improved with CM310 compared with placebo. In addition, CM310 significantly relieved the daily symptoms of patients with CRSwNP and improved their quality of life reflected by the improvements in the TSS (-2.6 [95% CI -3.5, -1.6]), UPSIT (10.4 [95% CI 6.8, 14.0]) and SNOT-22 score (-19.1 [95% CI -29.8, -8.5]). Compared with placebo, CM310 administration significantly reduced type 2-related biomarkers including the serum TARC and total IgE, and tissue eosinophils. The most common adverse events were upper respiratory tract infection, blood cholesterol increased, and tinnitus, but none were considered drug-related. Interpretation: These findings support CM310 as an effective additional treatment option to the standard of care in patients with severe ECRSwNP. Funding: KeyMed Biosciences (Chengdu) Limited.

Competition between skin antimicrobial peptides and commensal bacteria in type 2 inflammation enables survival of S. aureus.

During inflammation, the skin deploys antimicrobial peptides (AMPs) yet during allergic inflammation it becomes more susceptible to Staphylococcus aureus. To understand this contradiction, single-cell sequencing of Il4ra-/- mice combined with skin microbiome analysis reveals that lower production of AMPs from interleukin-4 receptor α (IL-4Rα) activation selectively inhibits survival of antibiotic-producing strains of coagulase-negative Staphylococcus (CoNS). Diminished AMPs under conditions of T helper type 2 (Th2) inflammation enable expansion of CoNS strains without antibiotic activity and increase Staphylococcus aureus (S. aureus), recapitulating the microbiome on humans with atopic dermatitis. This response is rescued in Camp-/- mice or after topical steroids, since further inhibition of AMPs enables survival of antibiotic-producing CoNS strains. In conditions of Th17 inflammation, a higher expression of host AMPs is sufficient to directly inhibit S. aureus survival. These results show that antimicrobials produced by the host and commensal bacteria each act to control S. aureus on the skin.

Analysis of short-term efficacy and safety of the first subcutaneous injection of dupilumab in the treatment of moderate-to-severe childhood atopic dermatitis / 中华皮肤科杂志

Objective:To investigate short-term efficacy and safety of subcutaneous injection of dupilumab in the treatment of moderate-to-severe childhood atopic dermatitis (AD) .Methods:A retrospective study was conducted on clinical data from children who were diagnosed with moderate-to-severe AD and subcutaneously injected with dupilumab in Department of Dermatology, Beijing Children′s Hospital, Capital Medical University from March 2021 to August 2021. Changes in the Eczema Area and Severity Index (EASI), itch Numeric Rating Scale (NRS) score, SCORing Atopic Dermatitis (SCORAD) index, and Dermatology Family quality of life Index (DFI) were analyzed before and 4 weeks after the first subcutaneous injection of dupilumab. Adverse events were collected during the first injection to the first follow-up visit at week 4 after the start of treatment. Normally distributed measurement indices were compared by using paired t test, non-normally distributed measurement indices were compared by using signed rank test, and logistic regression analysis was used to evaluate the effects of disease duration, eosinophil counts, IgE levels, personal and family history of allergic diseases on EASI50 (≥ 50% decrease in the EASI score) after dupilumab treatment. Results:A total of 39 children were enrolled in this study, including 21 males and 18 females. Twenty-one patients were aged 2 to < 6 years, 18 were aged 6 to < 18 years, and their median age ( Q1, Q3) was 65.0 (53.0, 111.0) months. Four weeks after the single-dose subcutaneous injection of dupilumab, 18 patients (84.85%) achieved ≥ 50% decrease in EASI score, 13 (60.61%) ≥ 75% decrease in EASI score; 18 (75.76%) experienced a decrease of ≥ 4 points in peak NRS, and 20 (81.82%) ≥ 3 points in peak NRS; the SCORAD score decreased by ≥ 50% in 15 (68.75%) patients, and by ≥ 75% in 7 (18.75%). Neither common adverse events such as conjunctivitis, skin infections, injection site reactions, nor serious adverse events were observed in any of the children from the first injection to the first follow-up visit at week 4. Logistic regression analysis showed no significant effect of the disease duration, eosinophil counts, IgE levels, personal or family history of allergic diseases on EASI50 (all P > 0.05) . Conclusion:A single-dose subcutaneous injection of dupilumab can markedly improve pruritus and severity of skin lesions in children with moderate-to-severe AD, and enhance the family quality of life, with favorable short-term safety.

IL-4Rα deletion disrupts psychomotor performance and reference memory in mice while sparing behavioural phenotype associated with spatial learning.

Contribution of immune mediators, interleukin-4 and interferon gamma to cognitive functioning is receiving increasing attention. However, the fundamental question about how heterodimeric interleukin-4 receptor alpha- and interferon gamma- producing myeloid cells converge to influence hippocampal-dependent spatial memory tasks through immunomodulation of multisensory inputs from other brain areas remains unexplored. Here, we show that mice lacking interleukin-4 receptor alpha are able to successfully learn spatial tasks, while reference memory is impaired. Moreover, the absence of interleukin-4 receptor alpha leads to simultaneous increase in proportions of CD11b + myeloid cells in the hippocampus and thalamus, but not the brainstem during acquisition. Interleukin-4 receptor alpha deletion significantly decreased expression of myeloid cell-derived interferon gamma in the thalamus during the acquisition phase and simultaneously increased brain-derived neurotrophic factor production in the thalamus and brainstem of trained mice. We provide evidence that interleukin-4 receptor alpha is essential for cognitive performance while training-induced alterations in interferon gamma activity and brain-derived neurotrophic factor signalling may contribute to neuromodulation of learned tasks and consequently affect systems-level memory encoding and consolidation.

The role of interleukin 4 and IL-4RA in intervertebral disc degeneration: investigation of single nucleotide polymorphisms in genes and a systematic review & meta-analysis of IL-4 expression level.

Background: Intervertebral disc degeneration (IVDD) is a multifactorial disease that is sensitive to the balance between anti-inflammatory and pro-inflammatory cytokines. This study investigated the single nucleotide polymorphisms (SNPs) of interleukin 4 (IL-4) in IVDD.Methods: Genomic DNA of peripheral mononuclear cells of 76 IVDD patients and 140 healthy controls were investigated for three SNPs of IL-4 (rs2243248 (-1098G/T), rs2243250 (-590 C/T), rs2070874 (-33 C/T)) and 1 SNP of IL-4RA (rs180275, +1902 A/G) through PCR-SSP method.Results: The 'C' allele frequency of IL-4 rs2243250 was 104 in 76 patients, while it was 149 in 140 controls (OR = 2, p = .001); also this SNP was significantly associated with post-operative pain reduction. The 'C' allele of IL-4 rs2070874 (130 in 76 patients, and 200 in 140 controls, OR = 2.66), and the 'CC' genotype were more frequent among patients (OR = 3.98, p < .001) than controls. 'TTT' haplotype was more common in controls (OR = 0.36, p < .001) and 'TCC' was also more common in patients (OR = 1.75, p = .012). A meta-analysis of previous studies found significantly higher IL-4 levels in disc tissues of IVDD patients, which was not similarly found in blood samples.Conclusion: The immune system plays an important role in IVDD. The extent and progress of the disease vary significantly with IL-4 level. Meanwhile, the rs2070874 and rs2243250 SNPs of IL-4 were significantly associated with IVDD in Iranian patients.

Interleukin-4 and Interleukin-4 Receptor Alpha Gene Polymorphisms in Recurrent Aphthous Stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral condition with a major impact on the quality of life. The condition is thought to be due to the overexpression of T helper-1(Th1)-related cytokines. Since interleukin-4 (IL-4) and its receptor (IL-4Rα) are antagonistic to Th-1 pathways, polymorphisms in their genes may also be involved in the pathogenesis of aphthous stomatitis. METHODS: Sixty-four patients diagnosed with minor RAS and 141 (age- and sex-matched) healthy controls were assessed for 3 single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-4 gene (-1098G/T, -590C/T, and -33C/T), and 1 SNP in IL-4Rα gene (+1902 A/G). RESULTS: No significant differences were detected between the patient and the control group regarding IL-4 allele frequencies. However, the patient group demonstrated a higher frequency of IL-4 -590 CC genotype and a lower rate of IL-4 -590 TC genotype. The TCT, GTT, GCT, and GTC haplotypes of the IL-4 gene (-1098, -590, -33) were significantly more frequent in the patients and the GCC, and TTT haplotypes were more common in healthy controls. No significant differences were found in IL-4Rα gene polymorphism between the 2 groups. CONCLUSIONS: Certain polymorphisms of IL4 gene could predispose individuals to RAS.

Neuronal IL-4Rα modulates neuronal apoptosis and cell viability during the acute phases of cerebral ischemia.

Ischemic stroke caused by an embolus or local thrombosis results in neural tissue damage (an infarct) in the territory of the occluded cerebral artery. Decades of studies have increased our understanding of the molecular events during cerebral infarction; however, translation of these discoveries to druggable targets for ischemic stroke treatment has been largely disappointing. Interleukin-4 (IL-4) is a multifunctional cytokine that exerts its cellular activities via the interleukin-4 receptor α (IL-4Rα). This cytokine receptor complex is associated with diverse immune and inflammatory responses. Recent studies have suggested a role of the cytokine IL-4 in long-term ischemic stroke recovery, involving immune cell activity. In contrast, the role of the receptor, IL-4Rα especially in the acute phase of infarction is unclear. In this study, we determined that IL-4Rα is expressed on neurons and that during the early phases of cerebral infarction (24 h) levels of this receptor are increased to regulate cellular apoptosis factors through activation of STAT6. In this context, we show a neuroprotective role for IL-4Rα in an in vivo surgical model of cerebral ischemia and in ex vivo brain slice explants, using both genetic knockout of this receptor and RNAi-mediated gene knockdown. IL-4Rα may therefore represent a novel target and pathway for therapeutic development in ischemic stroke.

Recombinant interleukin-4 alleviates mechanical allodynia via injury-induced interleukin-4 receptor alpha in spinal microglia in a rat model of neuropathic pain.

Glial cells play important roles in the development and maintenance of neuropathic pain. In particular, activated microglia in the spinal cord facilitate the hyper-excitability of dorsal horn neurons after peripheral nerve injury via pro-inflammatory molecules. In this study, we investigated the possible involvement of the anti-inflammatory cytokine, interleukin-4 (IL-4), in neuropathic pain. We did not detect the expression of IL-4 mRNA in the rat dorsal root ganglion or spinal cord; however, peripheral nerve injury induced the expression of IL-4 receptor (IL-4R) alpha mRNA in the spinal cord. A histological analysis revealed that nerve injury induced IL-4R alpha mRNA in activated spinal microglia ipsilateral to the injury site. Additionally, the increases in IL-4R alpha were coincident with the increased expression of phosphorylated signal transducer and activator of transcription 6 (pSTAT6) in spinal microglia. Intrathecal administration of recombinant IL-4 suppressed mechanical hypersensitivity in neuropathic rats, and the analgesic effect of IL-4 was accompanied by further enhancement of pSTAT6 expression in spinal microglia. Taken together, these results suggest that the adaptive responses of microglia to nerve injury involve both inflammatory and anti-inflammatory signaling, including IL-4R alpha and pSTAT6. These findings support that utilizing the endogenous anti-nociceptive activity of IL-4R alpha may modify the cell lineage of pro-nociceptive microglia, thus providing a novel therapeutic strategy for neuropathic pain.

Interleukin-4 Receptor Alpha: From Innate to Adaptive Immunity in Murine Models of Cutaneous Leishmaniasis.

The interleukin (IL)-4 receptor alpha (IL-4Rα), ubiquitously expressed on both innate and adaptive immune cells, controls the signaling of archetypal type 2 immune regulators; IL-4 and IL-13, which elicit their signaling action by the type 1 IL-4Rα/gamma common and/or the type 2 IL-4Rα/IL-13Rα complexes. Global gene-deficient mouse models targeting IL-4, IL-13, or the IL-4Rα chain, followed by the development of conditional mice and generation of important cell-type-specific IL-4Rα-deficient mouse models, were indeed critical to gaining in-depth understanding of detrimental T helper (Th) 2 mechanisms in type 1-controlled diseases. A primary example being cutaneous leishmaniasis, which is caused by the protozoan parasite Leishmania major, among others. The disease is characterized by localized self-healing cutaneous lesions and necrosis for which, currently, not a single vaccine has made it to a stage that can be considered effective. The spectrum of human leishmaniasis belongs to the top 10 infectious diseases according to the World Health Organization. As such, 350 million humans are at risk of infection and disease, with an incidence of 1.5-2 million new cases being reported annually. A major aim of our research is to identify correlates of host protection and evasion, which may aid in vaccine design and therapeutic interventions. In this review, we focus on the immune-regulatory role of the IL-4Rα chain from innate immune responses to the development of beneficial type 1 and detrimental type 2 adaptive immune responses during cutaneous Leishmania infection. We discuss the cell-specific requirements of the IL-4Rα chain on crucial innate immune cells during L. major infection, including, IL-4Rα-responsive skin keratinocytes, macrophages, and neutrophils, as well as dendritic cells (DCs). The latter, contributing to one of the paradigm shifts with respect to the role of IL-4 instructing DCs in vivo, to promote Th1 responses against L. major. Finally, we extend these innate responses and mechanisms to control of adaptive immunity and the effect of IL-4Rα-responsiveness on T and B lymphocytes orchestrating the development of CD4+ Th1/Th2 and B effector 1/B effector 2 B cells in response to L. major infection in the murine host.

Association of IL4 single-nucleotide polymorphisms with febrile seizures.

As of importance of interleukin-4 (IL-4) in inhibiting the production of proinflammatory cytokines, the IL4 gene polymorphisms were investigated in patients with febrile seizure. This association has not been investigated yet, except 1 study which has been done in Japanese population. Eighty-two patients with febrile seizure were enrolled in this study, compared with 139 controls. The allele and genotype frequency of 3 single-nucleotide polymorphisms of IL4 gene were determined. Frequency of the IL4-590/C allele in the patient group was significantly higher than in the control group (P < .0001). Frequency of the following genotypes was significantly lower in patients compared to controls: IL-4 (-590) TC (P = .0001) and IL-4 (-33) TC (P = .001). The most frequent IL-4 haplotype in the patient group was TCC (P = .00) haplotype. In contrast, frequencies of GCC (P = .01), TTT (P = .009), and TTC (P = .0007) haplotypes were significantly lower in febrile seizure patients. Certain alleles, genotypes, and haplotypes in the IL4 gene were overrepresented in Iranian patients with febrile seizure, which could predispose individuals to this disease, and further investigations in other ethnicities are required.

Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells.

An increasing number of studies is focusing on the role of myeloid-derived suppressor cells (MDSCs) in the suppression of antitumor immune responses. Although the main site of action for MDSCs is most likely the tumor microenvironment, the study of these cells has been largely restricted to MDSCs derived from peripheral lymphoid organs. Only in a minority of studies MDSCs isolated from the tumor microenvironment have been characterized. This review will give an overview of the data available on the phenotypical and functional differences between tumor-derived MDSCs and MDSCs isolated from the spleen of tumor-bearing mice or from the peripheral blood of cancer patients.