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[Display omitted] • ABF1 is induced by ABA and promotes ABA repression on rice flowering. • SAPK8 phosphorylates ABF1 and strengthens the latter participating in ABA-mediated flowering inhibition. • ABA enhances the direct transcriptional repression of ABF1 on Ehd1 and Ehd2. • ABF1 recruits PRC2 complex to deposit H3K27me3 to suppress Ehd1 and Ehd2. Rice flowering is a major agronomic trait, determining yield and ecological adaptability in particular regions. ABA plays an essential role in rice flowering, but the underlying molecular mechanism remains largely elusive. In this study, we demonstrated a "SAPK8-ABF1- Ehd1/Ehd2 " pathway, through which exogenous ABA represses rice flowering in a photoperiod-independent manner. We generated abf1 and sapk8 mutants using the CRISPR-Cas9 method. Using yeast two-hybrid, Pull down, BiFC and kinase assays, SAPK8 interacted and phosphorylated ABF1. ABF1 directly bound to the promoters of Ehd1 and Ehd2 using ChIP-qPCR, EMSA, and LUC transient transcriptional activity assay, and suppressed the transcription of these genes. Under both long day and short day conditions, simultaneous knock-out of ABF1 and its homolog bZIP40 accelerated flowering, while SAPK8 and ABF1 over-expression lines exhibited delayed flowering and hypersensitivity to ABA-mediated flowering repression. After perceiving the ABA signal, SAPK8 physically binds to and phosphorylates ABF1 to enhance its binding to the promoters of master positive flowering regulators Ehd1 and Ehd2. Upon interacting with FIE2, ABF1 recruited PRC2 complex to deposit H3K27me3 suppressive histone modification on Ehd1 and Ehd2 to suppress these genes transcription, thereby leading to later flowering. Our work highlighted the biological functions of SAPK8 and ABF1 in ABA signaling, flowering control and the involvement of a PRC2-mediated epigenetic repression mechanism in the transcription regulation governed by ABF1 on ABA-mediated rice flowering repression. [ABSTRACT FROM AUTHOR]

Trichloroethylene-induced hypersensitivity dermatitis (TIHD) is a delayed hypersensitivity response that is affected by genetic and environmental factors. Occupational exposure to trichloroethylene (TCE) enhances antigen presentation, leading to hypersensitivity in workers with the HLA-B* 13:01 allele. Several studies have observed the activation of herpesviruses, such as Epstein Barr virus (EBV), in TIHD patients. However, the underlying mechanisms remain unclear. Toll-like receptors (TLRs) play a pivotal role in the pathogenesis of herpesvirus infection. This study aimed to explore whether TLRs serve as a shared mechanism for both herpesvirus and allergenic chemicals. In this study, HLA-B* 13:01-transfected Hmy2. A C1R cell model was constructed, and cells were treated with TCOH and EBV to explore the possible mechanisms. We established a mouse model of dermatitis and used a TLR4 agonist to verify the effect of herpesvirus on TIHD. The results showed that EBV and TCOH synergistically enhance antigen processing and presentation via the TLR2/NF-κB axis. Furthermore, TLR4 agonist further aggravated skin lesions and liver damage in TCE-sensitized mice through TLR4/NF-κB axis-mediated antigen processing and presentation. Together, this study indicates that viral infection further aggravates the inflammatory response in TIHD based on environment-gene interactions. • Trichloroethanol and EBV synergistically activated TLR2/NF-κB pathway. • Trichloroethanol and EBV promoted antigen processing and presentation. • TLR4 agonist aggravated trichloroethylene-induced antigen-presenting function. • TLR4 agonist potentiated the skin lesions of trichloroethylene-sensitized mice. [ABSTRACT FROM AUTHOR]

• Vaccine excipient-positive BAT associates with delayed hypersensitivity manifestations. • DMG-PEG 2000 reactivity is frequent in patients with anti-SARS-CoV-2 vaccine hypersensitivity. • DMG-PEG 2000 reactivity associates with vaccination. Basophil activation test (BAT) can tackle multiple mechanisms underlying acute and delayed hypersensitivity to drugs and vaccines and might complement conventional allergy diagnostics but its role in anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-related hypersensitivity is ill-defined. Therefore, 89 patients with possible hypersensitivity (56 % with delayed mucocutaneous manifestations) to anti-SARS-CoV-2 vaccines were tested with BAT for Macrogol 3350, DMG-PEG 2000, PEG 20000, polysorbate-80 and trometamol and compared to 156 subjects undergoing pre-vaccine BAT. A positive BAT was associated with delayed reaction onset (p = 0.010) and resolution (p = 0.011). BAT was more frequently positive to DMG-PEG 2000 than to other excipients in both groups (p < 0.001). DMG-PEG 2000 reactivity was less frequent in vaccine-naïve (6 %) than vaccinated subjects (35 %, p < 0.001) and associated with mRNA-1273 vaccination. DMG-PEG 2000 BAT might therefore have a diagnostic role in subjects with delayed hypersensitivity reactions. Natural immunity might be a key player in basophil activation. [ABSTRACT FROM AUTHOR]

• Vero cell culture-derived Japanese encephalitis vaccine (JE-VC; Ixiaro) was approved for adults in 2009. • We retrospectively evaluated adverse events of special interest following JE-VC, including hypersensitivity and neurologic events. • Data from U.S. military personnel who received JE-VC were compared to data from recipients of Vi capsular polysaccharide typhoid vaccine, a vaccine with a favorable safety profile. • The risk of adverse events of special interest was similar between groups, supporting the safety of JE-VC. Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC; Ixiaro) was approved in the United States in 2009. The previous JE vaccine, an inactivated mouse brain-derived vaccine, had been associated with rare, but serious, allergic and neurologic adverse events (AE). Studies and AE surveillance have supported JE-VC's safety, but one evaluation among military personnel found elevated hypersensitivity and neurologic AE rates. However, co-administration of multiple vaccines to some personnel might have affected results. We retrospectively compared rates of hypersensitivity and neurologic AEs within 28 days following vaccination of military personnel with JE-VC or parenteral Vi capsular polysaccharide typhoid vaccine administered without other vaccines from July 1, 2011, through August 31, 2019. Rates of most events were similar between the vaccines. Only delayed hypersensitivity reactions occurred more frequently following JE-VC (rate ratio: 4.2, 95 % CI 1.2–15.3; p = 0.03), but rates were low for both vaccines. These results support JE-VC's safety. [ABSTRACT FROM AUTHOR]

Phenazopyridine is an azo dye, which exerts local anesthetic or analgesic action on urinary tract mucosa through an unknown mechanism. Besides its common complications including orange discoloration of the urine and gastrointestinal problems, it may have rare side effects like hemolytic anaemia, methemoglobinemia, renal failure, and skin changes. We reported a paraplegic man with skin ulcers on scretom and right foot after about 3 days of phenazopyridine use A 62-year-old man presented with flesh shaped deep ulcers in lower parts of the body. He declared that at first a bluish discoloration was developed in the lower extremities and scrotum skin after use of eight phenazopyridine tablets (200 mg) and then these lesions turned to blisters and ulcers and they were prurient. The patient underwent sonography and CT-angiography; however, no pathologic findings were found. He just received losartan for many years as past drug history. According to the history, a delayed drug hypersensitivity reaction was suspected and the patient wounds healed after using special type of dressings and antibiotic therapy regarding positive wound cultures. Phenazopyridine severe skin changes are hardly reported. We described a case who experienced severe skin reactions and ulcers following phenazopyridine use not related to other complications including renal dysfunction, methemoglobinemia, and hemolytic anemia. [ABSTRACT FROM AUTHOR]

Stevens−Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening spectra of mucocutaneous delayed hypersensitivity reactions. Prodromal viral-like symptoms are followed by a characteristic diffuse rash caused by keratinocyte apoptosis and epidermal detachment. Three adolescents were admitted with SJS/TEN and vulvovaginal involvement following initiation of lamictal, bactrim, and phenobarbital. The patients received intravenous immunoglobulin and intravenous steroids. One patient received etanercept. Topical emollients and strict perineal hygiene were initiated. No permanent sequelae were noted following vaginoscopy. Vulvovaginal involvement in SJS/TEN can occur and may result in permanent architectural changes. Basic management includes withdrawal of causative medication, intravenous steroids, intravenous immunoglobulin (IVIG), and supportive care. Early initiation of perineal hygiene, vaginal barrier creams, and menstrual suppression should be employed. Vaginoscopy may be used to document full recovery. [ABSTRACT FROM AUTHOR]

Background: Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized.Objective: To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines.Methods: A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination.Results: From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions.Limitations: Registry analysis does not measure incidence. Morphologic misclassification is possible.Conclusions: We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination. [ABSTRACT FROM AUTHOR]

Drug-induced hypersensitivity reactions attributed to the immunosuppressive agent tacrolimus after an organ transplant are rare in the literature. We present 3 cases of male adult patients grafted with a cadaveric liver who developed delayed hypersensitivity reactions to tacrolimus in the form of the prolonged-release capsules (Advagraf). Furthermore, the appropriate drug concentration solutions used for allergy testing are proposed. All patients received a liver transplant (LT) because of cirrhosis of various etiologies. They were immunosuppressed with tacrolimus once daily. Several months after they had been placed on an immunosuppressive regimen with tacrolimus in the form of prolonged-release capsules (Advagraf), the patients presented with delayed hypersensitivity reactions and torturous pruritic rash that affected the whole body and was unresponsive to treatment with oral ursodeoxycholic acid, cholestyramine, or levocetirizine. Allergy testing that was performed by skin prick testing was negative. Nevertheless, intradermal testing yielded positive results in all 3 patients. Management was by interruption of the culprit agent, which was followed by symptom resolution. The immunosuppressive treatment was continued with alternative drugs. Appropriate nonirritating drug concentration solutions of the drug used for intradermal testing were highly sensitive and confirmed the clinical diagnosis of tacrolimus allergy in all the affected patients. Immunosuppressive treatment with tacrolimus in the form of prolonged-release capsules may cause a drug hypersensitivity reaction. A suspicion of allergy warrants a referral for allergy testing. Pruritic rash refractory to treatment in liver transplanted patients should be evaluated by an allergist for possible drug allergy when bile stasis and graft disease have been excluded. Intradermal testing has proven a highly sensitive method for confirming a drug allergy diagnosis, whereas skin prick testing did not. [ABSTRACT FROM AUTHOR]

• Vaccination rate for COVID-19 in Brazil is one of the highest in the world. • Additional vaccination for new variants, including omicron, will be necessary. • The country ranks second in aesthetic procedures worldwide. • Hypersensitivity to hyaluronic acid after COVID-19 vaccine administration is observed. • Aesthetic professionals should be aware and advise patients of this possibility. Brazil ranked second in the world for the number of aesthetic procedures carried out in 2019. Five case reports of delayed hypersensitivity reaction to hyaluronic acid dermal filler after COVID-19 vaccination are presented in this paper. Additional vaccination for new variants, including omicron, will be necessary; therefore, aesthetic professionals should be aware of this possibility and advise patients accordingly. [ABSTRACT FROM AUTHOR]

Les réactions d'hypersensibilité retardée (HSR) sont définies comme celles qui surviennent plus de six heures après une exposition aux allergènes et font intervenir l'immunité à médiation cellulaire. La peau est l'organe le plus souvent atteint dans les HSR aux produits naturels ou de synthèse ainsi qu'aux médicaments. La plupart des éruptions cutanées sont bénignes et spontanément résolutives, mais certaines sont graves, entraînant un risque élevé de morbidité et de mortalité. Elles doivent être reconnues tôt et gérées rapidement. La démarche diagnostique repose sur une anamnèse exhaustive, des tests in vivo tels que l'intradermoréaction retardée, le patch-test ou le test de provocation orale et des tests biologiques in vitro explorant l'activité de lymphocytes T spécifiques. Les performances de ces tests varient selon les manifestations cliniques. Les avancées concernant l'immunopathogenèse ont permis d'identifier des allèles HLA associés aux manifestations cliniques et ainsi de déterminer des facteurs de prédisposition. Cet article décrit les caractéristiques et la place actuelle de ces tests selon les phénotypes d'HSR. Delayed hypersensitivity reactions (DHR) are defined as reactions that occur more than 6 hours after exposure to small reactive molecules or drugs. The skin is the most often affected organ. Potentially life-threatening severe cutaneous adverse reactions (SCAR) are associated with a high risk of morbidity and mortality. They should be recognized and managed early by clinicians. The diagnostic workup is based on a precise anamnesis, a history of past events, in vivo tests such as delayed intradermal testing, patch-test or oral challenge and in vitro biological tests exploring the specific lymphocyte activity. Advances in understanding the delayed T cell–mediated reactions lead to identification of predisposing of HLA alleles. We describe the performance of these tests regarding the HSR phenotypes. [ABSTRACT FROM AUTHOR]

Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell–mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS. Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10−8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10−16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01–positive group indicated that 19.2% had DRESS and did so within 4 weeks. HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics. [ABSTRACT FROM AUTHOR]

Abstract Fluoroquinolones trigger anaphylaxis during clinical applications, affecting the safety of their administration. Mast cells are immune cells that act as sentinels during host defenses, mediating hypersensitivity and anaphylactic reactions. Mas-related G protein-coupled receptor X2 (MRGPRX2) is a mast cell-specific receptor that mediates cell degranulation in anaphylactic reactions. In this study, the mechanism underpinning the anaphylactic reactions caused by fluoroquinolones was investigated. Hypersensitivity was assessed through hindpaw swelling, tissue fluid leakage assays, in vivo and body temperature measurements assay in vivo, and cell calcium mobilization assays, and mast cell degranulation assays in vitro. Mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice and MrgprB2 (the orthologous receptor of MRGPRX2 in mice) knockout mice exhibited reduced fluoroquinolone-induced anaphylactic effects. Fluoroquinolones activated mast cells in a dose-dependent manner and reduced degranulation was observed following MRGPRX2 silencing. These results reveal that fluoroquinolone-induced anaphylactic reactions are mediated by mast cells through MRGPRX2. Graphical abstract Unlabelled Image Highlights • The mechanism underpinning the anaphylactic reactions caused by fluoroquinolones is proposed. • Mast cell-deficient KitW-sh/W-sh mice and MrgprB2 knockout mice exhibited reduced anaphylactic effects compared with WT mice. • Fluoroquinolones activated mast cells dose-dependently and reduced degranulation was observed following MRGPRX2 silencing. • The mechanism relies on fluoroquinolones-triggered mast cells activation via MRGPRX2. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A series of 1 H -pyrazolo[3,4- d ]pyrimidin-4-amino derivatives has been synthesized and identified as potent JAK2 inhibitors. • 11g had 36-58 fold selectivity against two other JAK-family proteins JAK1 and JAK3. • Compounds (11f , 11g) displayed higher potency against the leukemia cell line TF-1 than tofacitinib. • 11g displayed stronger antiproliferative activity against the spleen cell than tofacitinib. Abstract Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1 H -pyrazolo[3,4- d ]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3,5-disubstituted-1 H -pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors 11f , 11g , 11h and 11k displayed strong activity and selectivity against the JAK2 kinase, with IC 50 values of 7.2 nM, 6.5 nM, 8.0 nM and 9.7 nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound 11g also in cells. Furthermore, compound 11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Chronic fatigue syndrome (CFS) is known as a multi-systemic and complex illness, which induces fatigue and long-term disability in educational, occupational, social, or personal activities. The diagnosis of this disease is difficult, due to lacking a proper and suited diagnostic laboratory test, besides to its multifaceted symptoms. Numerous factors, including environmental and immunological issues, and a large spectrum of CFS symptoms, have recently been reported. In this review, we focus on the nutritional intervention in CFS, discussing the many immunological, environmental, and nutritional aspects currently investigated about this disease. Changes in immunoglobulin levels, cytokine profiles and B- and T- cell phenotype and declined cytotoxicity of natural killer cells, are commonly reported features of immune dysregulation in CFS. Also, some nutrient deficiencies (vitamin C, vitamin B complex, sodium, magnesium, zinc, folic acid, l -carnitine, l -tryptophan, essential fatty acids, and coenzyme Q 10) appear to be important in the severity and exacerbation of CFS symptoms. This review highlights a far-driven analysis of mineral and vitamin deficiencies among CFS patients. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A strategy using HPLC-HRMS with multivariate statistical analysis to discover toxic potential markers of triptolide was developed. • Forty-six triptolide metabolites were identified in the liver, kidney and plasma, and 27 of them might be related to toxicity. • Two metabolites in the plasma were showed potential as the early diagnosis markers for triptolide toxicity. • Metabolic pathways of therapeutic and toxic dose triptolide in DTH model mice were constructed. Abstract Triptolide (TP) is the crucial active ingredient of Tripterygium glycoside tablets and has been shown to have a significant therapeutic effect on delayed-type hypersensitivity (DTH)-related diseases. However, due to its potential hepatotoxicity and nephrotoxicity, adverse reactions have often been observed in long-term treatment regimens. Therefore, it is meaningful to find metabolic markers for toxicity for early diagnosis. In this study, a feasible strategy using HPLC-HRMS method combined with multivariate statistical analysis to discover toxic potential markers of TP was developed. TP was used to treat a DTH mouse model at a therapeutic dose (45μg/kg) and toxic dose (900 μg/kg). The metabolic profiles of the liver, kidney and plasma were characterized by HPLC-Q/TOF MS. Significant differences in the metabolite profiles of the liver, kidney and plasma existed between the toxic and therapeutically dosed mice. Forty-six metabolites were identified and 27 of them may be related to toxicity based on a structure-toxicity prediction model. Using OPLS-DA analysis, the metabolite profiles between the two dose groups could be well distinguished. It was found that 18, 4 and 4 metabolic markers were altered in the liver, kidney and plasma, respectively; 15, 4 and 3 of these metabolic markers were predicted to be toxic. Two toxic markers detected both in mouse plasma and human liver microsomes following incubation with TP showed great potential as early diagnosis markers for TP hepatotoxicity and nephrotoxicity. [ABSTRACT FROM AUTHOR]

Over the last few decades, the pyrethroid insecticide bifenthrin has been increasingly employed for pest control in urban and agricultural areas, putting humans and wildlife at increased risk of exposure. Exposures to nanomolar (nM) concentrations of bifenthrin have recently been reported to alter calcium oscillations in rodent neurons. Neuronal calcium oscillations are influenced by ryanodine receptor (RyR) activity, which modulates calcium-dependent signaling cascades, including the mechanistic target of rapamycin (mTOR) signaling pathway. RyR activity and mTOR signaling play critical roles in regulating neurodevelopmental processes. However, whether environmentally relevant levels of bifenthrin alter RyR or mTOR signaling pathways to influence neurodevelopment has not been addressed. Therefore, our main objectives in this study were to examine the transcriptomic responses of genes involved in RyR and mTOR signaling pathways in zebrafish ( Danio rerio ) exposed to low (ng/L) concentrations of bifenthrin, and to assess the potential functional consequences by measuring locomotor responses to external stimuli. Wildtype zebrafish were exposed for 1, 3 and 5 days to 1, 10 and 50 ng/L bifenthrin, followed by a 14 d recovery period. Bifenthrin elicited significant concentration-dependent transcriptional responses in the majority of genes examined in both signaling cascades, and at all time points examined during the acute exposure period (1, 3, and 5 days post fertilization; dpf), and at the post recovery assessment time point (19 dpf). Changes in locomotor behavior were not evident during the acute exposure period, but were observed at 19 dpf, with main effects (increased locomotor behavior) detected in fish exposed developmentally to bifenthrin at 1 or 10 ng/L, but not 50 ng/L. These findings illustrate significant influences of developmental exposures to low (ng/L) concentrations of bifenthrin on neurodevelopmental processes in zebrafish. [ABSTRACT FROM AUTHOR]

Résumé L’allergie aux bêtalactamines est une situation fréquente car environ 10 % des malades se disent allergiques à la pénicilline. Cependant ce diagnostic est largement porté par excès. Derrière cette notion d’allergie on distingue les hypersensibilités immédiates pouvant conduire au choc anaphylactique et les hypersensibilités retardées, du plus fréquent exanthème maculo-papuleux aux toxidermies bulleuses sévères ou DRESS pouvant mettre en jeu le pronostic vital. La réalisation d’un bilan allergologique comportant des tests cutanés orientés selon le tableau clinique, complétés de tests de provocation orale en l’absence de contre-indication, va permettre de confirmer ou infirmer ce diagnostic et d’identifier en cas d’allergie confirmée, les alternatives sures au sein des bêtalactamines. Allergy to beta-lactam antibiotics is a common condition and about 10% of patients report being allergic to penicillin. However, this diagnosis is largely overestimated. Two types of allergy should be distinguished and include immediate hypersensitivity that can lead to anaphylactic shock and delayed hypersensitivity, ranging from the most common maculopapular exanthema to severe bullous toxidermia or life-threatening DRESS. Allergy challenge with oriented skin tests according to the clinical features, supplemented with oral challenge in the absence of contraindication, will confirm or invalidate the diagnosis of beta-lactam allergy and will help to identify if necessary safe alternatives to beta-lactams. [ABSTRACT FROM AUTHOR]

Vaccines against human papilloma virus (HPV) have been demonstrated to be very effective to prevent infection-related neoplasms. However, several reports describing heterogeneous post-vaccination phenomena have been published in last few years. The spectrum of these disorders includes both immune-mediated neurological diseases and neuropsychiatric functional disorders. Some researchers speculated about a genetic predisposition, but others hypothesized a role of adjuvants, including some metals and, particularly, aluminum. Here, we tested sixteen young girls developing somatoform and neurocognitive syndromes after the HPV immunization, through MELISA® test, detecting cell-mediated hypersensitivity to several metals. We found no association between these neurocognitive disorders and the results provided by this test; importantly, no patients showed hypersensitivity to aluminum, which is the inorganic adjuvant included in HPV vaccines. Thus, if aluminum played a role in the pathophysiology of musculoskeletal and neurocognitive disturbances occurring in some young girls after HPV immunization, that should recognize other mechanisms than the activation of aluminum-specific lymphocytes. [ABSTRACT FROM AUTHOR]

Physical or psychological chronic stress can suppress the immune system. However, the mechanisms remain to be elucidated. We investigated the effect of hematopoietic stem-progenitor cells (HSPCs) on chronic stress-induced the alterations of immune responses. We demonstrate that HSPCs prevents stress-induced lymphocyte apoptosis. Moreover, we also demonstrate that the protective effect of HSPCs on stress-induced lymphocyte reduction exerts by steroid hormones. Furthermore, we reveal that chronic stress-induced T cell-mediated immune responses contributes to the protective effect of HSPCs. These results indicate that HPSCs might offer a novel therapeutic strategy against the deleterious effects of chronic stress on the immune system. [ABSTRACT FROM AUTHOR]

Ethephon can liberate ethylene which could interfere the plant growth process. The aim of the present study was to determine the effect of ethephon on developing immune system of male offspring. Ethephon could enhance NK cell activity in male mice. For 4-week-old male mice, lymphocytes of peripheral blood increased while the hemolytic plaque number decreased. Delayed type hypersensitivity(DTH) was inhibited in all groups. The expression of protein Bcl11b and p-p38 in thymus of treatment groups were lower than control group. Our results indicated that cellular immunity of male offspring is more sensitive to ethephon when exposed in pregnancy and lactation period. It should be emphasized that exposure to ethephon during the in utero stage and lactation stage still could damage the immune function of animal in the period before fully mature even in the dosage that could not influence the immune function of adult animal. [ABSTRACT FROM AUTHOR]

Résumé Les hypersensibilités retardées aux bêtalactamines (BL) ne sont pas forcément allergiques. Ainsi, leur exploration est primordiale pour ne pas contre-indiquer à tort cette classe d'antibiotiques très utile. L'exploration des hypersensibilités retardées aux BL comporte plusieurs étapes : tout d'abord l'interrogatoire minutieux avec réalisation d'une frise chronologique des prises médicamenteuses depuis 2 mois. Puis la réalisation de tests cutanés : des patch-tests plus ou moins des intradermoréactions à lecture retardée (en cas d'anamnèse compatible avec patch-tests négatifs) voire des tests biologiques (en cas de diagnostic difficile). En cas de tests négatifs, on discutera la réalisation d'un test de réintroduction. En cas de tests cutanés positifs, on recherchera les alternatives thérapeutiques au sein des bêtalactamines en réalisant une batterie de tests puis des réintroductions. Abstract Delayed hypersensitivity to beta-lactams (BL) is not necessarily allergic. It is thus essential to explore such cases of hypersensitivity to avoid unwarranted contraindication of this class of antibiotics. Exploring delayed hypersensitivity to BL involves a number of steps. First, careful questioning is called for with recording of all drugs taken in the previous two months. Skin tests must then be performed consisting of patch tests, and if necessary, intradermal tests (in the case of a compatible history but negative patch tests), or possibly laboratory tests (in the event of diagnostic difficulties). If the skin tests are negative, a challenge test should be considered. With positive tests, alternative beta-lactams should be introduced and then challenged. [ABSTRACT FROM AUTHOR]

A series of novel scopariusicide derivatives were designed and synthesized starting from the main diterpenoid from the aerial parts of Isodon scoparius. Sis-25 was the most effective compound among them. The potential mechanism(s) of its immunosuppressive activity in vitro , as well as its effects on delayed type hypersensitivity (DTH) reaction and imiquimod-induced dermatitis in vivo were investigated in this study. Sis-25 inhibited anti-CD3/anti-CD28 mAbs, PHA or alloantigen-induced T cell proliferation without obvious cytotoxicity. Sis-25 was a highly selective inhibitor of GSK3-β and inhibited the mTOR/p70S6K pathway but not the PI3K/Akt, p38 MAPK/ERK 1/2 and JAK3/STAT5 pathways. Furthermore, Sis-25 significantly inhibited IFN-γ, IL-6 and IL-17 expression but not IL-10 expression in activated T cells. Finally, Sis-25 treatment mitigated the DNFB-induced DTH reaction and ameliorated imiquimod-induced dermatitis. In summary, Sis-25 exerted significant immunosuppressive activity by targeting GSK3β in vitro and in vivo. Sis-25 may guide the design of new drugs for more effective and safer treatments of autoimmune diseases and provide new insight into developing utilizations of Isodon scoparius. [Display omitted] • Sis-25 inhibits T cell proliferation without obvious cytotoxicity. • Sis-25 is identified as a highly selective inhibitor of GSK3-β. • Inhibition of GSK3-β by its inhibitor LiCl or SB415286 promotes T cell activation, but inhibits T cell proliferation. • Sis-25 treatment mitigates DNFB-induced DTH reaction and ameliorates imiquimod-induced dermatitis. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Radix Astragali (RA), Radix Angelicae Sinensis (RAS) and Folium Epimedii (FE) are three of the extensively applied herbs among traditional Chinese medicines for gynecological disorders and osteoporosis. A derivative herbal formula—RRF, consisting of the three medicines with a weight ratio of 5:1:5, is derived from a famous Chinese herbal formula—Danggui Buxue Tang (DBT). RRF has shown noteworthy perimenopause ameliorating effect in both ovariectomized rats and natural aging female rats, which might represent a promising candidate for the treatment of perimenopausal disorders. The aim of this study was to evaluate its immunological potential, chronic toxicity and reproductive effects by 26-week repeated daily administration in female rats, in order to optimize its safe use. Materials and methods The effect of RRF on immunological function was studied by macrophage phagocytosis, immune organ index, serum immunoglobulin level as well as delayed type hypersensitivity (DTH) in mice. For toxicity assessment, acute toxicity study was performed according to fixed dose procedure with a single oral administration of RRF to mice. In the oral chronic toxicity, 120 female rats were administrated RRF orally in 0, 1100, 4400, or 8800 mg/kg/day doses for 26 weeks. Clinical signs, mortality, body weights, feed consumption, haemato-biochemical parameters, organ weights, histopathology and reproductive hormone profiles were examined at the end of the 13- and 26-week dosing period, as well as after the 4-week recovery period. Results Oral administration of RRF at three doses (282, 564 and 1128 mg/kg) significantly increased the indices of phagocytosis K , as compared with prednisone acetate (PR) group ( p <0.05 or 0.01). Exposure of RRF dose-dependently boosted circulating serum IgM level (all p <0.01) in response to CRBC in PR - induced mice. Furthermore, RRF treatment elicited a significant increment (all p <0.01) in DNFB-induced DTH response and the immune organ indices in a dose-dependent manner in mice, in parellel to DNFB-induced group. In the single dose acute toxicity and repeated dose 90-day chronic toxicity investigations, no toxic signs/mortality were observed. RRF treatment did not cause any toxicologically significant changes in clinical signs, food consumption, body weight, relative organ weight, hematological parameters, clinical chemistry, gross pathology and histopathology between treatment and control groups. No treatment related gross/histopathological lesions were observed and no target organ was identified. Long-term repeated administration of RRF exerted a significant promotion on serum level of steroid hormone estradiol, progesterone and testosterone release, along with decrease of circulating pituitary follicle stimulating hormone, luteinizing hormone, and prolactin levels in female rats. The No Observed Adverse Effect Level (NOAEL) of RRF was determined to be over 8800 mg/kg/day for elderly female rats, a dose that was equivalent to 50 times of human dose. Conclusion The present investigation demonstrated that RRF possessed appreciable immunopotentiating activity and had a relatively wide margin of safety. Long-term treatment of RRF exhibited estrogenic properties, and retarded certain age-associated degenerations. RRF might have the potential for further development as a safe and effective alternative/complementary to conventional medication in relieving perimenopausal symptoms. [ABSTRACT FROM AUTHOR]

Search for novel specific antigens are urgently needed for the detection of tuberculosis (TB). In this study, we evaluated the diagnostic potential of a novel Mycobacterium tuberculosis (M.tb)-specific candidate antigen (Rv2645) from DNA segment region of differentiation (RD) 13 of M.tb and investigated T-cell recognition during natural infection in humans and experimental mice. Rv2645-specific IFN-γ levels were much higher in the peripheral blood mononuclear cells (PBMCs) of TB patients than that in healthy donors (HDs) (including Bacille Calmette-Guerin (BCG)-vaccinated donors). The enzyme-linked immunospot (ELISPOT) assay with Rv2645 had a high overall agreement (98.0%) with the results from the clinical T-SPOT.TB with 10-kD culture filtrate protein (CFP10) and 6-kD early secreted antigenic target (ESAT6) peptides. The combination of Rv2645 and CFP10-ESAT6 was better than the individual protein, with increased sensitivity and a similar specificity of 96.0% and 98.2%, respectively. Rv2654 also induced M.tb-specific skin-test responses in heat-inactivated M.tb H37Rv immunized mice. Epitope mapping revealed that Rv264530-44 and Rv2645136-143 may be the dominant T-cell and B-cell epitopes, respectively, of Rv2645. This is the first report demonstrating the Rv2654 is a strongly recognized T-cell antigen that is highly specific for TB and has potential as a novel cell-mediated immunity-based TB diagnostic agent. [ABSTRACT FROM AUTHOR]

Impulsivity is described as one of the main risk factors for mania. One facet of impulsivity, the inability to delay gratification, might be of special relevance, because a hypersensitivity to reward is hypothesized to be related to mania. The main aim of this study was to examine whether risk for mania is associated with deficits in the ability to delay gratification using both a behavioral and a self-report (UPPS) measure. An additional reason for choosing the UPPS was to see if prior results about an association between risk for mania and positive urgency could be replicated. Thirty-three individuals at risk for mania and a matched control group were selected using the Hypomanic Personality Scale and interviewed for a history of mood disorders. The main outcome measures were the Single-Key-Impulsivity-Paradigm and Monetary Choice Questionnaire. The groups did not differ in measures of gratification delay but we replicated other studies reporting significantly higher levels of positive urgency and sensation seeking in at-risk individuals. We suggest that individuals at risk might not generally be more impulsive but rather that impulsive behaviors might be triggered in response to specific mood states. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine the effect of immune status, age and genetic background on the induction of oral tolerance to Actinomyces viscosus . Suppression of delayed type hypersensitivity (DTH) response and antigen-specific serum antibody levels could be induced in DBA/2 mice intragastrically and systemically immunized with A. viscocus , suggesting the induction of oral tolerance. In contrast, this immune suppression could be abrogated if the animals had been systemically immunized prior to the induction of oral tolerance with the same bacterium. Long-term systemic immunization prior to intragastric immunization with A. viscocus suppressed DTH response only. Cell transfer of this group of animals also suppressed DTH response in the donors, indicating the action of suppressor cells for inhibition of DTH response. Furthermore, oral tolerance to A. viscocus failed to occur in mice aged at 3 days and 1, 2, 4, 6 and 36 weeks old. Mice bearing H-2 d haplotype were the most susceptible to oral tolerization, followed by H-2 b and H-2 k . Therefore, the results of the presence study suggest that the induction of oral tolerance to A. viscosus in mice may be dependence on the immune status and genetic background but not age. [ABSTRACT FROM AUTHOR]

Neonatal to early childhood is the critical period for establishing a balance of T helper 1 (Th1) versus T helper 2 (Th2) cellular immunity within the gut, which is strongly influenced by the source and establishment of gut microflora. Probiotic administration has been shown to attenuate Th2-biased cellular immunity and predisposition to food allergies. To test this hypothesis we provided ad libitum a probiotic-supplemented (Primalac 454 Feed Grade Microbials) or control diet to lactating dams with suckling pups and weaned pups until 10 weeks of age. Weaned mice were sensitized/challenged with peanut extract, saline or adjuvant at 6, 8 and 10 weeks of age. At 3, 6, 8 and 10 weeks, fecal samples were collected for microbial analysis, while blood samples were analyzed for total plasma IgE levels. At termination (10 weeks of age), splenic T lymphocyte population subtypes were determined using FACS analysis and Th1/Th2/Th17 gene expression by PCR array. Mice given the probiotic-supplemented diet had significantly enhanced probiotic fecal counts compared to controls at 3, 6, 8 and 10 weeks. Moreover, mice fed the probiotic-supplemented diet had enhanced splenic naturally occurring T regulatory cell populations, and reduced splenic gene expression of allergic mediator IL-13 compared to controls. These results provide evidence that early probiotic supplementation may provide host protection to hypersensitivity reactions to food allergens by attenuating food allergen inflammatory responses. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) is a major global burden in part due to the underlying pathophysiological mechanisms being poorly understood. A LBP rat model involving two injections of nerve growth factor (NGF, an endogenous pain-related neurotrophin) into trunk musculature was recently developed. Additional behavioral work in this NGF-LBP rat model is required to better characterize local and remote somatosensory alterations related to NGF-induced peripheral and central sensitization. This work characterizes the time-dependent development of hypersensitivity to trunk and hindpaw cutaneous mechanical stimulation and deep muscle mechanical hyperalgesia in adult male Sprague-Dawley rats (n = 6/group). Behavioral assays were performed at baseline (Day 0, D0), D2, D5 (pre- and 4 h post-2nd NGF or control injection), D7, D10, and D14 in NGF and control groups. Trunk and hindpaw cutaneous mechanical hypersensitivity were tested using von Frey filaments. Deep trunk mechanical hyperalgesia was determined using a small animal algometer. NGF rats demonstrated increased cutaneous sensitivity to ipsilateral trunk mechanical stimuli at D7, D10, and D14. NGF rats also demonstrated ipsilateral deep mechanical hyperalgesia on D2, D5 + 4 h, D7, D10, and D14. Cutaneous hypersensitivity was delayed compared to deep hyperalgesia in NGF rats. No additional sensory changes were noted. Together, these results indicate that male mechanical somatosensory changes develop primarily locally in the ipsilateral trunk following unilateral NGF injections. These findings contrast with a previous report in female rats using this NGF-LBP model showing more widespread (bilateral) hyperalgesia and remote mechanical hypersensitivity. Future studies will examine potential sex-related pain behavioral differences in the NGF model. • NGF-induced LBP resulted in ipsilateral cutaneous and deep trunk mechanical hypersensitivity in male rats. • NGF-induced LBP in male rats failed to induce hindpaw mechanical hypersensitivity. • Deep trunk mechanical sensitivity preceded the development of cutaneous trunk sensitivity. • NGF-induced LBP mirrors mechanical sensitivity reported in clinical low back pain. [ABSTRACT FROM AUTHOR]

Highlights: [•] Responsiveness to HBV vaccine and DTH testing can predict HIV disease progression. [•] We evaluated HBV vaccine seroresponses in those with non-anergic DTH results. [•] HBV vaccine response predicted AIDS or death even in non-anergic persons with HIV. [Copyright &y& Elsevier]

Abstract: Background: Degradable polymer drug-eluting stents (DP-DES) represent a promising strategy to improve the delayed healing and hypersensitive reaction in the vessel. However, the efficacy and safety of DP-DES vs. permanent polymer drug-eluting stents (PP-DES) are less well defined. The aim of this meta-analysis was to compare the total, short (<30days), mid (30days–1year) and long (>1year) term outcomes of DP-DES vs. PP-DES. Methods: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials to compare any of approved DP- and PP-DES. Efficacy endpoints were target-lesion revascularization (TLR) and in-stent late loss (ISLL). Safety endpoints were death, myocardial infarction (MI), and composite of definite and probable stent thrombosis (ST). Results: The meta-analysis included 19 RCTs (n=18,395) with interesting results. As compared with DES, there was a significantly reduced very late ST (OR [95% CI]=0.42 [0.24–0.77], p=0.852) and ISLL (OR [95% CI]=−0.07 [−0.12–0.02], p=0.000) in DP-DES patients. However, there were no differences between DP-DES and PP-DES for other safety and efficiency outcomes, except that the stratified analysis showed a significant decreased TLR with DP-DES as compared to paclitaxel-eluting stent (OR [95% CI]=0.41 [0.20–0.81], p=0.457). Conclusions: DP-DES are more effective in reducing very late ST and ISLL, as well as comparable to PP-DES with regard to death, TLR and MI. Further large RCTs with long-term follow-up are warranted to better define the relative merits of DP-DES. [Copyright &y& Elsevier]

Abstract: We examined the effect of fingolimod (0.1 and 0.3 mg/kg/day orally) on blood–brain barrier (BBB) function, demyelination and leukocyte recruitment at different stages of the focal delayed-type hypersensitivity (DTH) multiple sclerosis model in Lewis rats using immunohistochemistry and gadolinium (Gd)-enhancing magnetic resonance imaging (MRI). During DTH lesion formation, fingolimod reduced BBB breakdown (52%; p = 0.05), and lymphocyte (53%; p = 0.016) and macrophage/activated microglia (49%; p = 0.002) recruitment to the DTH lesion compared with vehicle-treated controls. Following DTH lesion establishment, fingolimod reduced the area of BBB breakdown (75%; p = 0.04), lymphocyte recruitment to the DTH lesion (41%; p = 0.01) and activated microglia outside of the lesion core (p = 0.01), but did not reduce recruitment of macrophages/activated microglia within the DTH lesion. During the chronic disease phase, when the BBB was resealed, fingolimod reduced the area of demyelination by 43% (p = 0.019) compared with vehicle-treated controls, while not affecting lymphocyte recruitment within the lesion. Fingolimod had different beneficial effects during different stages of DTH, reducing BBB breakdown and lesion development/brain tissue damage whilst reducing lymphocyte recruitment when BBB breakdown was apparent, but reducing demyelination independent of lymphocyte infiltration behind an intact BBB. These results suggest a direct CNS effect of fingolimod in this model. [Copyright &y& Elsevier]

Highlights: [•] DFNM has a particle size less than 25nm. [•] The particles were found to be superparamagnetic. [•] The DFNMs were biocompatible with more than 80% viable. [•] Non-skin irritant after skin sensitization in G. Pigs. [•] Not altered the antioxidant potential in vitro and in vivo. [Copyright &y& Elsevier]

Highlights: [•] HANP was synthesized by chemical method. [•] Characterized of HANP by TEM, SEM, FT-IR, XRD. [•] The HANPs were biocompatible with more than 80% viable. [•] Non-skin irritant after skin sensitization in G. pigs. [•] Not altered the antioxidant potential in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract: 2,3-Dichloro-1-propanol (2,3-DCP) is a member of a group of chemicals known as chloropropanols. Currently, immunotoxicity of 2,3-DCP has not been reported. In the present study, we studied its inhibitory effects on T cell both in vivo and in vitro. The results showed that 2,3-DCP markedly inhibited ConA-induced splenocyte proliferation, Th1 and Th2 cytokine production, CD4+ T cell populations, and the ratio of CD4+/CD8+ T cells and cell cycle arrest in vitro. In addition, 2,3-DCP markedly suppressed DNFB-induced T-cell-mediated delayed-type hypersensitivity (DTH) reaction in mice. Furthermore, Western blot was used to study how 2,3-DCP affects signal transduction mechanisms. The data revealed that 2,3-DCP could down regulate activation of ConA-induced NF-κB and NFAT signal transduction pathways. These observations indicated that 2,3-DCP exhibited negative regulatory effects by directly suppressing T-cell-mediated immune responses in vitro and in vivo. [Copyright &y& Elsevier]

Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34–65years) dosed once daily for 30days either with 30mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty-eight days postvaccination, seroconversion (anti-HAV IgG titer≥10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (±SE) titers were 27.3±5.5 and 21.4±4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123. [ABSTRACT FROM AUTHOR]

Abstract: Breeding dairy cattle using diverse phenotypic markers has been suggested as a feasible approach to improve health and decrease the deleterious consequences of infectious diseases. Studies conducted in pigs have demonstrated the value of antibody (AMIR)- and cell (CMIR)-mediated immune responses as quantitative traits for improving immune responsiveness by selecting livestock using estimated breeding values (EBV) for immune response (IR) traits. Studies of cattle have tested the possibility of using IR traits as phenotypic markers to classify cows as high (HR), average (AR) and low (LR) responders. Information is scarce or unavailable about either genetic parameters of AMIR and CMIR or their phenotypic and genetic associations with production, conformation, fertility or health traits in lactating dairy cattle. The objectives of the current study were to evaluate phenotypic and genetic parameters of both AMIR and CMIR as quantitative immunological traits (n =6) in comparison with production, fertility and health traits in dairy cattle for their use in a selection index intended to improve bovine health. Results of this study showed significant AMIR and CMIR responses. Most phenotypic correlations between IR traits and production, health or fertility traits were not significant. The highest heritabilities (h 2) were observed for delayed-type hypersensitivity (DTH) to killed Candida albicans whole cell (CaWC) at 48h (0.54) and AMIR day 14 (0.42). The highest genetic correlations were observed between AMIR 14 and AMIR 21 (0.99) and between DTH to CaWC 24h and DTH to CaWC 48h (0.93). Two important and significant sire EBV correlations were noted between AMIR and fat % (0.18), and between CMIR and protein % (−0.15). In conclusion, this study demonstrated that both AMIR and CMIR are heritable traits in cattle and could be considered for their inclusion in a selection index intended to improve health. [Copyright &y& Elsevier]

Abstract: Artemisinin and its derivatives have been reported to have immunosuppressive activity in some laboratory studies. However, the detail of mechanism remains to be demonstrated. The objective of this study is to clarify the immunosuppressive activity of artesunate (AST), one kind of artemisinin derivatives, and to find its unexplored mode of action. In vitro, the proliferation of T lymphocytes and its cytotoxicity were measured by WST-1 and MTT assay. In vivo, the immunomodulatory effect of AST was evaluated in a mouse model of delayed type hypersensitivity reaction (DTH), which was based on a T cell-mediated immune response. The data displayed that AST had a relatively high immunosuppressive activity with low toxicity, and could inhibit T lymphocyte proliferation induced by mitogen and alloantigen. Meanwhile, topical administration of AST could suppress DTH response significantly. Moreover, AST could also increase the secretion of TFG-β, coupling with the striking enhance of NF-κB/p65 and Smad2/3 signaling. The promotion of CD4+CD25+ regulatory T cells (Tregs) was shown to be a possible mechanism involved in AST-mediated regulation. Taken together, these observations exhibit the potential of developing AST as a novel safe remedy for the treatment of T cell-mediated immune disorders. [Copyright &y& Elsevier]

Abstract: Farrerol, a new type of 2,3-dihydro-flavonoid, has been isolated from the leaves of Rhododendron dauricum L. In the present study, we found that farrerol exerted potent immunosuppressive effects on murine T cells both in vitro and in vivo. In vitro, farrerol markedly suppressed concanavalin A (ConA)-induced lymphocyte proliferation, Th1 and Th2 cytokine production, cluster of differentiation 4-positive (CD4+) T cell populations, and the ratio of CD4+/cluster of differentiation 8-positive (CD8+) T cells. Moreover, farrerol significantly inhibited the T cell-mediated delayed-type hypersensitivity (DTH) reaction in vivo. In addition, we investigated signal transduction mechanisms to determine the effects of farrerol by Western blotting. The data revealed that farrerol could downregulate the activation of the nuclear factor κB (NF-қB) and nuclear factor of activated T cells 2 (NFAT2) signal transduction pathways. These findings suggested that farrerol has potential effects on the regulation of the immune system and could be developed as a practicable immunosuppressive compound. [Copyright &y& Elsevier]

Abstract: Nguni cattle are known to be more resistant to ticks than Bonsmara cattle, even if the immunological mechanisms responsible for this phenomenon are not fully understood. Cutaneous hypersensitivity responses to unfed larval extracts (ULE) of the ticks Rhipicephalus decoloratus and Rhipicephalus microplus were investigated in Nguni and Bonsmara cattle to improve knowledge on the immunity to ticks. Hypersensitivity reactions were induced by intradermal inoculation of 0.1ml of ULE of R. decoloratus and R. microplus ticks (50μg protein) in the right and left ear, respectively, of 8–9-month-old Nguni (n =11) and Bonsmara (n =9) heifers. Ear thickness was measured using callipers before and 0.5, 1, 6, 24, 48, and 72h post inoculation (PI). Bonsmara cattle showed a more intense immediate reaction with maximum response at 1h PI and no delayed hypersensitivity reaction. Nguni heifers, conversely, presented a less intense immediate reaction with maximum response at 1h PI, and a delayed hypersensitivity reaction at 72h PI. Reactions to R. decoloratus ULE produced a more intense skin response than to R. microplus in both breeds at all time intervals. Nguni cattle showed lower tick infestation indicating higher tick resistance than Bonsmara cattle. Delayed hypersensitivity reaction could be associated with superior tick resistance in the Nguni breed, while immediate hypersensitivity reaction could be associated with increased tick susceptibility in the Bonsmara breed. This study indicates the need for further investigations on the correlation of tick resistance and cellular immune responses to tick infestation in Nguni cattle. [Copyright &y& Elsevier]

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Abstract: Introduction of antigen into anterior chamber (AC) induces a deviant immune response termed anterior chamber-associated immune deviation (ACAID) that protects the eye from inflammatory destruction consequent to a systemic immune response. Mesenchymal stem cells (MSCs) can modulate a variety of immune responses. However, the effects of systemic administration of MSCs on ACAID have not been explored. In this study, C57BL/6 mice were inoculated with ovalbumin in the AC to induce ACAID, control group received AC injection of solvent alone. Immediately after the AC injection, the mice were injected through the tail vein with human Umbilical Cord-derived MSCs (hUC-MSC) or phosphate buffer saline. All animals were subcutaneously immunized with ovalbumin one week later. Delayed-type hypersensitivity assay was performed another week following immunization. The splenic monocytes were then isolated, cultured and stimulated with ovalbumin. Levels of IL-10, TGF-β, and IFN-γ in culture media were measured by ELISA. The frequencies of CD4+CD25+Foxp3+ and CD8+Foxp3+ regulatory T cells (Tregs) were determined by flow cytometry. The results showed that the AC inoculation of ovalbumin induced significantly less ear swelling than controls, confirming the establishment of ACAID. MSCs potentiated IL-10 and TGF-β production, further suppressed IFN-γ secretion from splenic monocytes in ACAID mice, and enhanced expansion of CD4+CD25+Foxp3+ and CD8+Foxp3+ Tregs isolated from the spleen of ACAID mice. Therefore, our study, for the first time, provides clear evidence that systemic administration of MSCs augments cytokine production and Treg expansion from ACAID spleens, which may contribute to promotion and maintenance of ACAID. [Copyright &y& Elsevier]

Abstract: Background: Ingested immunoactive proteins, type I IFN, SIRS peptide 1–21, α-MSH, ACTH, and SST inhibit clinical attacks and inflammation in acute EAE by decreasing Th1-like cytokines, increasing Th2-like cytokines or increasing Treg cell frequencies. Objective: We examined whether another protein, neuropeptide Y, would have similar anti-inflammatory effects in EAE after oral administration. Design/methods: B6 mice were immunized with MOG peptide 35–55 and gavaged with control saline or NPY during ongoing disease. Splenocytes from mock fed or NPY fed mice were adoptively transferred into active MOG peptide 35–55 immunized recipient mice during ongoing disease. Results: Ingested (oral) NPY inhibited ongoing disease, and decreased inflammation. Adoptively transferred cells from NPY fed donors protected against actively induced disease and decreased inflammation. In actively fed mice, oral NPY decreased Th1-like cytokines and increased Th2-like IL-13 cytokines in both the spleen and the CNS. In recipients of donor cells from NPY fed mice there was a reduction of Th1 and Th17 and induction of Th2-like IL-13 cytokines in both the spleen and CNS. Oral NPY decreased clinical score and decreased inflammatory foci in both actively fed and recipients of actively fed mice. There was no significant increase in Treg cell frequencies in actively fed or recipients of NPY fed donor cells. Conclusions: Ingested (orally administered) NPY can inhibit clinical disease, inhibit CNS inflammation by decreasing Th17 and Th1-like cytokines and increasing Th2-like cytokines in the CNS. [Copyright &y& Elsevier]

Abstract: Stephanthraniline A (STA) isolated from the stems of Stephanotis mucronata (Blanco) Merr. was evaluated for their suppression on T cells'' immune responses in vitro and in vivo. In vivo, oral administration of STA significantly inhibited T cell-mediated delayed-type hypersensitivity (DTH) response. In vitro, STA has inhibitory effects on T cell proliferation induced by CD3/CD28 cross-linking or Con A; additionally, CD4+ T cells are more sensitive to this inhibition than CD8+ T cells. STA also suppressed the production of cytokines (IL-2, IFN-γ, IL-4 and IL-17) and mRNA expression of the genes associated with T cell activation, proliferation and differentiation. Our data indicate that STA inhibits the proliferation of T cells by inducing cell cycle arrest but not inducing apoptosis. The inhibitory mechanism of STA on T cells was correlated with the gene change related to multi-signal transduction pathways. Furthermore, we also provided lines of evidence that STA, distinct from glucocorticoids, did not activate the glucocorticoid receptor. These findings would be beneficial for further understanding the therapeutic effects of S. mucronata in the treatment of autoimmune diseases. It also suggested the potential of the natural steroid STA as the effective candidate compounds for use in the treatment of inflammatory and autoimmune diseases. [Copyright &y& Elsevier]

Abstract: Progesterone has been demonstrated to be involved in maintaining pregnancy by regulating immunocytes. Dendritic cells (DCs), the most potent triggers of the adaptive immune response, express receptors for steroid hormones and are regarded as one of the primary targets of progesterone. However, the functional modification of DCs by progesterone remains poorly understood. Here, we report that progesterone does not affect the morphology or apoptosis of murine bone marrow-derived DCs. Progesterone-treated DCs were characterized by decreased expression of Ia (MHC class II), CD80 and CD86, increased production of IL-10, and decreased secretion of IL-12. Compared with mature DCs (mDCs), activated progesterone-treated DCs had a reduced capacity to stimulate CD4+ T cell proliferation. The observation that progesterone-treated DCs could attenuate delayed-type hypersensitivity (DTH) responses in vivo suggests that progesterone mediates suppressive DC activity. However, transfer of progesterone-treated DCs into the peritoneal cavity of mice did not elevate the percentage of CD4+CD25+Foxp3+ regulatory T cells in the spleen. Overall, our study helps to increase understanding of the role of DCs exposed to progesterone in the maintenance of pregnancy. [Copyright &y& Elsevier]

Abstract: Developmental immunotoxicity assessment is considered ready for inclusion in developmental toxicity studies. Further evaluation of proposed and additional assays is needed to determine their utility in assessing developmental immunotoxicity. In this study, a wide range of immunological parameters was included in an extended one-generation reproductive toxicity protocol. F0 Wistar rats were exposed to DOTC via the feed (0, 3, 10, and 30mg/kg) during pre-mating, mating, gestation and lactation and subsequently F1 were exposed from weaning until sacrifice. Immune assessments by several immune parameters were performed at PNDs 21, 42 and 70. The T cell-dependent antibody response to Keyhole Limpet hemocyanin (KLH) was assessed following subcutaneous immunizations with KLH on PNDs 21 and 35 and the delayed-type hypersensitivity response (DTH) against KLH was evaluated at PND 49. No effects were found on PND 21. While effects on lymphocyte subpopulations in the thymus were only observed in the 30mg/kg group on PND 42, effects on lymphocyte subpopulations in the spleen were found in the 30mg/kg group on both PNDs 42 and 70. The DTH response already showed an effect at 3mg/kg and was the overall critical endpoint. The results from this study support the inclusion of splenocyte subpopulation parameters in developmental toxicity studies and identified the DTH response as an important functional parameter. [Copyright &y& Elsevier]

Delayed-type hypersensitivity (DTH) is marked by high levels of protein antigen-specific T cell responses in sensitized individuals. Recent evidence has revealed a distinct pathway for T cell immunity directed against glycolipid antigens, but DTH to this class of antigen has been undetermined and difficult to prove due to their insolubility in aqueous solutions. Here, glucose monomycolate (GMM), a highly hydrophobic glycolipid of the cell wall of mycobacteria, was dispersed in aqueous solutions in the form of octaarginine-modified liposomes and tested for its ability to elicit cutaneous DTH responses in bacillus Calmette-Guerin (BCG)-immunized guinea pigs. After an intra-dermal challenge with the GMM liposome, a significant skin induration was observed in BCG-immunized, but not mock-treated, animals. The skin reaction peaked at around 2 days with local infiltration by mononuclear cells, and therefore, the response shared basic features with the classical DTH to protein antigens. Lymph node T cells from BCG-immunized guinea pigs specifically increased IFN-γ transcription in response to the GMM liposome, and this response was completely blocked by antibodies to CD1 lipid antigen-presenting molecules. Finally, whereas the T cells increased transcription of both T helper (Th) 1-type (IFN-γ and TNF-α) and Th2-type (IL-5 and IL-10) cytokines in response to the purified protein derivative or tuberculin, their GMM-specific response was skewed to Th1-type cytokine production known to be critical for protection against tuberculosis. Thus, our study reveals a novel form of DTH with medical implications. [ABSTRACT FROM AUTHOR]

Abstract: Human skin is exposed to a large variety of cosmetic allergens. Most allergic contact dermatitis occurs after exposure to fragrance, preservatives, and hair dyes. Such reactions can often be occult. As a result, a high index of suspicion is needed in assessing the patient with facial or cosmetic dermatitis. This contribution looks at why such a large number of chemicals are in everyday usage, at how dermatologists monitor trends in allergy to cosmetics, and at a number of new and emerging allergens to consider in the assessment of suspected cosmetic allergy. [Copyright &y& Elsevier]

Abstract: Insulin reactions occur rarely but are of tremendous clinical importance. The first was reported in 1922 as a callus reaction at the injection site of insufficiently purified bovine insulin. Porcine insulin was subsequently found to be less allergenic than bovine insulin. Increasingly pure insulins have decreased the risk of adverse reactions, and the production of recombinant insulin with the same amino sequence as human insulin saw a large decrease in adverse reactions. Currently, the prevalence of allergic reactions to insulin products appears to be approximately 2%, and less than one-third of these events have been considered related to the insulin itself. Other reactions occur due to the preservatives added to insulin, including zinc, protamine, and meta-cresol. Allergic reactions can be type I or immunoglobulin E-mediated, type III or Arthus, and type IV or delayed-type hypersensitivity reactions. Type I reactions are the most common and can, rarely, cause anaphylaxis. In contrast, type IV reactions can occur after a delay of several days. Investigations include skin prick testing, patch testing, intradermal testing, and occasionally, skin biopsy. [Copyright &y& Elsevier]