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SARS CoV-2 virus has infected more than 200 million people worldwide and more than 4.4 million in Indonesia. The vaccination program has become one of the solutions launched by many countries globally, including Indonesia, to reduce the transmission rate of COVID-19. Various vaccination platforms are produced, such as inactivated, viral vector, mRNA, and protein subunit. The vaccination booster program with mRNA platform (Moderna) was launched by the Indonesian government to give better protection for health care workers, particularly from delta variant. In this case report, we discuss one of the typical side effects of Moderna vaccine, which is referred to as the COVID arm.

Background: Recent studies demonstrated that, in the past few years, the number of jellyfish species is increasing worldwide; this increase can be explained by environmental and climatic reasons. Contacts with jellyfish can cause acute and chronic effects, including allergic reactions. Although anaphylaxis caused by jellyfish is a rare event, repetitive stings during bathing as well as marine sports and job activities represent important risk factors that can increase the probability of sensitization. Recently, it was also pointed out the possibility of anaphylaxis caused by jellyfish ingestion. In these cases, the sensitization could also be related to previous stings. In cases in which there is no history of jellyfish contact or ingestion, it has been hypothesized that there is a sensitization to an unknown cross-reactive antigen. Objective: The purpose of this work was to collect and review published studies and cases of anaphylaxis associated with jellyfish. Methods: We performed a medical literature data base search, which included English language articles published until September 2019, by using the key words "jellyfish" associated with "anaphylaxis" or "anaphylactic shock." Results: The results of our research showed that dangerous reactions can be caused both by contact and ingestion. Moreover, the latest changes in food habits, life style, and globalization could lead to a more frequent exposure to jellyfish both by contact and ingestion, and, consequently, to a higher probability of sensitization. Conclusion: Prospective studies and well-structured research are needed to better understand all the potential immunologic elements of jellyfish, to clarify its role in sensitization, and to avoid possible dangerous allergic reactions caused by cross-reactivity.

Background: Anaphylaxis-like reactions developing within a few minutes are the most frequent complications of subcutaneous or submucosal injections of local anaesthetics (LAs), and topically applied LAs are potential contact allergens. In addition, injected LAs have been reported to induce delayed reactions, including local inflammation at the injection site, and various general symptoms., Objectives: To assess the frequency and symptoms of late-type hypersensitivity occurring several hours after LA injections., Methods: We retrospectively evaluated clinical data and test results from all patients referred to our allergy clinic in a period of 20 years for diagnostic work-up of LA-associated late-type reactions., Results: Of 202 patients reporting symptoms with onset at least 1 hour after LA injection, 40 had cutaneous inflammation confined to the injection site, and 162 reported various systemic symptoms. LA hypersensitivity could be excluded in all patients with systemic complaints by means of skin testing and subsequent subcutaneous provocation. In 8 of the 40 patients (20%) with local inflammatory reactions, late-type allergic LA hypersensitivity was confirmed., Conclusions: Late-type LA allergy commonly causes inflammatory skin reactions confined to the injection site. Conversely, LAs are highly unlikely to trigger delayed systemic symptoms such as urticarial or exanthematous skin eruptions., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cyanoacrylate closure for the treatment of incompetent saphenous veins does not cause thermal damage and demonstrates satisfactory outcomes with rapid recovery. However, the characteristics of phlebitis-like abnormal reaction (PLAR), the most common adverse event after cyanoacrylate closure, have not been clarified. Moreover, it differs from typical phlebitis after thermal ablation. The objective of our study is to investigate the clinical features of PLAR after cyanoacrylate closure and to report its management., Methods: A total of 160 patients with 271 incompetent saphenous veins (great saphenous veins, 201; small saphenous veins, 70) underwent cyanoacrylate closure with the VenaSeal™ system. We defined PLAR as any unusual skin condition that develops suddenly, such as erythema, itching, swelling, and pain/tenderness, over the treated veins several days after cyanoacrylate closure. Oral antihistamines and intravenous dexamethasone were administered to manage PLAR., Results: Of the 271 treated veins, 69 experienced PLAR (25.4%). The mean time of occurrence was 13.6 ± 4.6 days after treatment. The rate of occurrence of erythema, itching, swelling, and pain/tenderness were 92.2%, 91.2%, 66.2%, and 48.5%, respectively. The occurrence of PLAR was significantly higher for great saphenous veins than for small saphenous veins (P < 0.001). Occurrences were more frequent in cases with a suprafascial great saphenous vein of length >10 cm than in cases with a subfascial great saphenous vein (P = 0.001). The proportion of patients who reported swelling decreased by more than half after the administration of oral antihistamine. The pain score on the 10th day also decreased significantly after the administration of antihistamine (P = 0.006)., Conclusions: PLAR must be distinguished from classic phlebitis. We believe that PLAR is a type IV hypersensitivity reaction due to a foreign body, and in our experience, antihistamines or steroids are effective for the prevention and management of PLAR., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Ultraviolet (UV) wavelengths in sunlight are the prime cause of skin cancer in humans with both the UVA and UVB wavebands making a contribution to photocarcinogenesis. UV has many different biological effects on the skin that contribute to carcinogenesis, including suppression of adaptive immunity, sunburn and altering the migration of mast cells into and away from irradiated skin. Many molecular mechanisms have been identified as contributing to skin responses to UV. Recently, using gene set enrichment analysis of microarray data, we identified the alternative complement pathway with a central role for factor B (fB) in UVA-induced immunosuppression. In the current study we used mice genetically deficient in fB (fB-/- mice) to study the functional role of the alternative complement pathway in skin responses to UV. We found that fB is required for not only UVA but also UVB-induced immunosuppression and solar-simulated UV induction of the oedemal component of sunburn. Factor B-/- mice had a larger number of resident skin mast cells than control mice, but unlike the controls did not respond to UV by increasing mast cell infiltration into the skin. This study provides evidence for a function role for fB in skin responses to UV radiation. Factor B regulates UVA and UVB induced immunosuppression, UV induced oedema and mast cell infiltration into the skin. The alternative complement pathway is therefore an important regulator of skin responses to UV.

Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal, and therefore establishing its cause is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Results of our studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern, and central United States; Europe; Australia; and parts of Asia. Typical immune responses to carbohydrates are considered to be T-cell independent, whereas IgE antibody production is thought to involve sequential class-switching that requires input from T cells. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Nexplanon® is an etonogestrel implant with a long-acting contraceptive effect. Although several studies underlined its safety profile, its implant can rarely lead to moderate or severe adverse event. Here, we presented a case of delayed-type hypersensitivity reaction against Nexplanon® that resolved after its removal., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Food allergy is defined as an adverse immune response towards food proteins or as a form of a food intolerance associated with a hypersensitive immune response. It should also be reproducible by a double-blind placebo-controlled food challenge. Many reported that food reactions are not allergic but are intolerances. Food allergy often presents to clinicians as a symptom complex. This review focuses on the clinical spectrum and manifestations of various forms of food allergies. According to clinical presentations and allergy testing, there are three types of food allergy: IgE mediated, mixed (IgE/Non-IgE), and non-IgE mediated (cellular, delayed type hypersensitivity). Recent advances in food allergy in early childhood have highlighted increasing recognition of a spectrum of delayed-onset non-IgE-mediated manifestation of food allergy. Common presentations of food allergy in infancy including atopic eczema, infantile colic, and gastroesophageal reflux. These clinical observations are frequently associated with food hypersensitivity and respond to dietary elimination. Non-IgE-mediated food allergy includes a wide range of diseases, from atopic dermatitis to food protein-induced enterocolitis and from eosinophilic esophagitis to celiac disease. The most common food allergies in children include milk, egg, soy, wheat, peanut, treenut, fish, and shellfish. Milk and egg allergies are usually outgrown, but peanut and treenut allergy tends to persist. The prevalence of food allergy in infancy is increasing and may affect up to 15-20 % of infants. The alarming rate of increase calls for a public health approach in the prevention and treatment of food allergy in children.

Introduction: Hypersensitivity reactions to beta-lactams (BLs) are often reported in children, with amoxicillin and, to a lesser extent, cephalosporins being the most frequent drugs involved. Although many of these children are considered to be allergic, a careful evaluation only confirms a low percentage., Objectives: To analyse the clinical data, sensitization profile and diagnostic methods used in a large group of children with a clinical history of hypersensitivity reactions to BLs., Methods: The study included children aged 1-14 yr with symptoms suggestive of hypersensitivity to BLs from January 2006-December 2012. Diagnosis was confirmed from a clinical history, specific IgE determination, skin testing and, if necessary, a drug provocation test (DPT)., Results: Of a total of 783 patients studied, only 62 (7.92%) were confirmed as being allergic, 9 (14.52%) with immediate and 53 (85.48%) with non-immediate reactions. In those with immediate reactions, 2 (22.22%) were diagnosed by in vitro test, 2 (22.22%) by skin testing and 5 (55.56%) by DPT; in those with non-immediate reactions, 2 (3.77%) were diagnosed by skin testing and 51 (96.23%) by DPT. In all cases, DPT was positive to the culprit drug (29 AX-CLV, 26 AX, 1 cefixime and 1 cefaclor), and the most usual symptoms were exanthema in 43 cases, urticaria in 12, urticaria-angio-oedema in 1 and erythema in 1 case., Conclusion: After an allergological work-up, over 90% of the children evaluated were finally confirmed as tolerant to BLs. Most reactions were of the non-immediate type, and DPT was an essential tool for diagnosis., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Purpose: The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) modulates the Ca(2+) response through the control of the membrane potential in the immune system. We investigated the role of K(Ca)3.1 on the pathogenesis of delayed-type hypersensitivity (DTH) in auricular lymph node (ALN) CD4(+) T-lymphocytes of oxazolone (Ox)-induced DTH model mice., Experimental Approach: The expression patterns of K(Ca)3.1 and its possible transcriptional regulators were compared among ALN T-lymphocytes of three groups [non-sensitized (Ox-/-), Ox-sensitized, but non-challenged (Ox+/-) and Ox-sensitized and -challenged (Ox+/+)] using real-time polymerase chain reaction, Western blotting and flow cytometry. KCa 3.1 activity was measured by whole-cell patch clamp and the voltage-sensitive dye imaging. The effects of K(Ca)3.1 blockade were examined by the administration of selective K(Ca)3.1 blockers., Key Results: Significant up-regulation of K(Ca)3.1a was observed in CD4(+) T-lymphocytes of Ox+/- and Ox+/+, without any evident changes in the expression of the dominant-negative form, K(Ca)3.1b. Negatively correlated with this, the repressor element-1 silencing transcription factor (REST) was significantly down-regulated. Pharmacological blockade of K(Ca)3.1 resulted in an accumulation of the CD4(+) T-lymphocytes of Ox+/+ at the G0/G1 phase of the cell cycle, and also significantly recovered not only the pathogenesis of DTH, but also the changes in the K(Ca)3.1 expression and activity in the CD4(+) T-lymphocytes of Ox+/- and Ox+/+., Conclusions and Implications: The up-regulation of K(Ca)3.1a in conjunction with the down-regulation of REST may be involved in CD4(+) T-lymphocyte proliferation in the ALNs of DTH model mice; and K(Ca)3.1 may be an important target for therapeutic intervention in allergy diseases such as DTH., (© 2013 The British Pharmacological Society.)

The adjuvant effect of icariin from Epimedium koreanum on the immune responses to bovine serum albumin (BSA) in mice was examined. Mice were immunized on days 1 and 22 intraperitoneally (i.p.) with one of the following: an emulsion form of BSA mixed with Incomplete Freund's Adjuvant (BSA/IFA) or with Complete Freund's Adjuvant (BSA/CFA) or BSA plus icariin mixed with IFA (BSA/Icariin/IFA). One week after the booster, polyclonal sera were collected from these animals to determine IgG isotypes specific for BSA in the sera and then spleens of these animals were harvested to evaluate IFN-γ and IL-4 produced in the splenocyte cultures. In order to determine the DTH (delayed type hypersensitivity) response, BSA was administered into the footpads of mice that were immunized as described above and the degree of footpad-swelling was measured. Data from these experiments showed that the icariin combined with BSA (BSA/Icariin/IFA) provoked the most abundant of IgG production in mice and enhanced the Th1-lineage development of IgG2a and IFN-γ productions (p < 0.05), whereas BSA/IFA resulted in a highest ratio of IgG1 to IgG2 and most dominant IL-4 production, indicating a Th2 response. This pattern of immunity was confirmed by the DTH determination revealing that icariin-containing formula caused the highest footpad-swelling followed by BSA/CFA and BSA/IFA, respectively. In addition, hemolytic assay showed that icariin at a dose of 1000 μg/mL caused no hemolysis when compared with a water-treated mouse. All of these data indicate that icariin has the immunoadjuvant effect which may enhance Th1-immune response, suggesting that icariin as an adjuvant would be beneficial in the treatment of Th1-disordered diseases.

Penicillins and cephalosporins are the most widely used antibiotics for the treatment of common infections, and they are the two main classes of β-lactams. On the basis of the time of appearance of the reaction after drug intake and for diagnostic purposes, hypersensitivity reactions to β-lactams have been classified as immediate or non-immediate. The diagnostic evaluation of allergic reactions to β-lactams has changed over the last decade, for several reasons. In many countries, major and minor determinants for skin testing are not available. In immediate allergic reactions, the sensitivity of skin testing is decreasing. For non-immediate reactions, skin testing appears to be less sensitive than previously reported. The drug provocation test is still necessary for diagnosis. In this education review series, we described three cases of β-lactam allergy: first, a child with an IgE-mediated allergy to benzyl-penicillin; second, a child with a non-allergic hypersensitivity to amoxicillin; and in the third patient, we will discuss about cross-reactivity between penicillins and cephalosporins. These cases are correlated with the practical management of evaluating β-lactam allergy., (© 2011 John Wiley & Sons A/S.)

Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p<0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p<0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity., (© 2011 John Wiley & Sons A/S.)

Background: Cross-reactivity between aztreonam and β-lactams is poor, but tolerability of aztreonam has been assessed in a few groups of patients suffering from IgE-mediated allergy to β-lactams. The aim of this study was to assess the cross-reactivity of aztreonam with other β-lactams and its tolerability in patients with cell-mediated allergy to these drugs., Methods: We studied 78 patients with cell-mediated allergy to β-lactams who underwent skin prick, immediate and delayed-reading intradermal tests as well as patch tests with penicilloyl-polylysine, minor determinant mixture, semi-synthetic penicillins, cephalosporins, aztreonam and imipenem. Patients with negative allergy testing with aztreonam underwent an intramuscular test dosing and were observed for 3 h., Results: Our patients experienced 94 non-immediate reactions; delayed-onset urticaria (34 cases), maculopapular exanthema (13 cases), urticaria/angioedema (15 cases) and itching erythema (13 cases) were the most reported symptoms. Amoxicillin (35 cases), ampicillin (28 cases) and bacampicillin (18 cases) were the most involved drugs. All patients had a positive patch test and/or a positive delayed-reading intradermal test to at least 1 β-lactam antibiotic and none had a positive patch or delayed-reading intradermal test to aztreonam. Then, 65 patients underwent intramuscular test dosing with aztroenam, and none of them had a clinical reaction., Conclusions: Our data confirm the lack of cross-reactivity between β-lactams and aztreonam in patients with cell-mediated allergy to these drugs. Delayed-reading intradermal tests and patch tests with aztreonam represent a simple and rapid diagnostic tool to establish tolerability in β-lactam-allergic patients., (Copyright © 2010 S. Karger AG, Basel.)

Osteopontin (OPN) is a phosphoglycoprotein that is expressed by various immune cells in a secreted and intracellular form. It has cytokine, chemotactic and cell signaling functions enhancing Th1 and Th17 immunity and protects against apoptosis. Recent studies found OPN to be modulatory in cell-mediated and immediate-type allergic diseases. In allergic asthma, OPN enhances sensitization but downmodulates Th2-driven IL-4-dominated inflammation. The finding that OPN expression is augmented during specific immunotherapy supports a Th2 suppressive effect of OPN. In Th1-driven delayed-type allergy, such as allergic contact dermatitis, OPN supports dendritic cell migration and IL-12 expression and is secreted by T effector cells and keratinocytes, augmenting Th1-mediated allergy and supporting disease chronification. There are numerous missing links as to how OPN variants modulate allergic inflammation through different OPN receptors. OPN research in allergy is an interesting, rapidly expanding field that has high potential for translational research.

Aim: to investigate the effects cannabidiol (CBD) on delayed-type hypersensitivity (DTH) reactions and antigen-induced T-cell cytokine expression., Methods: DTH was induced by subcutaneous ovalbumin (OVA) challenge to the footpads of mice sensitized with OVA. Inflammatory reactions were measured by footpad swelling and histological analysis. Antigen-induced cytokine expression by OVA-primed splenocytes was measured using ELISA and RT-PCR., Results: CBD (1-10 mg/kg) administration, in a dose-dependent fashion, significantly attenuated inflammatory reactions associated with DTH in the footpads of mice sensitized and challenged with OVA. Histological examination revealed that CBD suppressed the infiltration of T cells and macrophages, and the expression of interferon (IFN)-γ and tumor necrosis factor-α, two pro-inflammatory cytokines implicated in DTH in the inflammatory site. In contrast, the expression of interleukin (IL)-10 in the footpads was enhanced by CBD administration. In addition, CBD at concentrations devoid of cytotoxic effects (1-4 micromol/L) attenuated OVA-induced IFN-γ production by OVA-primed splenocytes, whereas IL-4 was unaffected., Conclusion: CBD curbs DTH reactions via suppressing the infiltration and functional activity of T cells and macrophages in the inflammatory site, suggesting a therapeutic potential for CBD for the treatment of type IV hypersensitivity.

We present a case of twin Hispanic male infants fed with cow's milk formula who presented at 3 weeks of life with nonbilious, nonbloody vomiting and diarrhea. Laboratory evaluation revealed leukocytosis, acidosis, and methemoglobinemia. Sepsis evaluation was negative. Although they recovered quickly with i.v. fluids, symptoms recurred again with ingestion of soy formula. An underlying diagnosis was sought that could explain their symptoms.

A 16-year-old Bangladeshi girl presented with a 9-day history of an extensive pruritic, erythematous, papulovesicular skin eruption to both forearms. Appearance was 5 days following application of a home-made henna preparation. Examination revealed ulceration and scabbing along the whole henna pattern and early keloid formation. A diagnosis of type IV delayed hypersensitivity reaction superimposed by infection was initially made. As in this case, home-made henna preparations commonly combine commercial henna with black hair dye, paraphenylenediamine (PPD). PPD, widely known as 'black henna', darkens the pigment and precipitates the drying process. PPD is a potent contact allergen associated with a high incidence of hypersensitivity reactions. Despite treatment the patient was left with extensive keloid scarring in the pattern of the henna tattoo.

Purpose of Review: To summarize the key literature and our research experience regarding Demodex infestation as a potential cause of ocular inflammatory diseases with a special emphasis on Demodex blepharitis., Recent Findings: Two distinct Demodex species have been confirmed as a cause of blepharitis: Demodex folliculorum can cause anterior blepharitis associated with disorders of eyelashes, and D. brevis can cause posterior blepharitis with meibomian gland dysfunction and keratoconjunctivitis. Tea tree oil treatments with either 50% lid scrubs or 5% lid massages are effective in eradicating mites and reducing ocular surface inflammation., Summary: Demodex blepharitis is a common but overlooked external eye disease. The pathogenesis of Demodex blepharitis in eliciting ocular surface inflammation has been further clarified. The modified eyelash sampling and counting method makes it easier and more accurate to diagnose Demodex infestation. Tea tree oil shows promising potential to treat Demodex blepharitis by reducing Demodex counts with additional antibacterial, antifungal, and anti-inflammatory actions.

beta-lactam antibiotics are the agents most frequently implied in immune drug adverse reactions. These can be classified as immediate or nonimmediate according to the time interval between the last drug administration and their onset. Mechanisms of immediate IgE-mediated reactions are widely studied and are therefore better understood. Nonimmediate reactions include a broad number of clinical entities like mild maculopapular exanthemas, the most common, and other less frequent but more severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute exanthematic pustulosis or cytopenias. These nonimmediate reactions are mainly mediated by T cells but the precise underlying mechanisms are not well elucidated. This fact complicates the allergological evaluation of patients with this type of reaction and available tests have demonstrated poor sensitivity and specificity.

The leaves of Cinnamomum tamala Linn. (CT) (Lauraceae) clinically used in Ayurveda as antidiabetic and diuretic, but no reports are available towards immunomodulating property. Its hexane fraction (CTH) was orally given to rats for 10 days and delayed type of hypersensitivity (DTH), antibody production against sheep red blood cells (SRBCs), mitotic index in bone marrow cells and concanavalin A (Con A) mediated proliferation of lymphocytes were assessed. Further on 30 days treatment, change in body weight (BW), spleen weight, thymus weight, bone marrow cellularity and hematological changes were observed. It inhibited significantly the DTH response (IC(50) 1475 +/- 57.19 mg kg(-1) BW), antibody production, suppressed mitotic index in bone marrow cells along with the suppression of lymphocyte proliferation against Con A (IC(50) 63.33 +/- 1.95 microg mL(-1)). In all experiments, cyclophasphamide and dexamethasone had been used as reference drug for in vivo and in vitro studies, respectively. On 30 days treatment, the CTH (800 mg kg(-1) BW and above) significantly suppressed growth rate, increase of spleen and thymus weight and low bone marrow cellularity. In hematological examination, it inhibited total white blood cell and lymphocytes count and increased per cent of polymorphs. Thus, it could be suggested that the fraction possesses immunosuppressive property at doses, higher than 800 mg kg(-1) BW in rats.

Food allergies are classified as IgE-mediated food allergies (IFAs) and non-IgE-mediated food allergies (NFAs). Recently, oral immunotherapy (OIT) has been found to be successful for treating both IFA and NFA, especially using interferon (IFN) gamma. This study was designed to clarify the clinical characteristics of IFA and NFA and compare the therapeutic characteristics of OIT using subcutaneously administered IFN-gamma for both types of food allergy. In this study, 148 patients were categorized into the IFA and NFA group following food challenge, skin-prick test and food-specific IgE tests. The patients were then treated using protocols specific for IFA and NFA using subcutaneous IFN-gamma injection as a randomized controlled trial. The principle of complete allergy resolution at prior dose in the case of IFA was also evaluated. Only the patients with IFA and NFA treated with OIT using IFN-gamma achieved tolerance successfully. Tolerance was achieved from low-dose range in IFA and in high-dose range for NFA. Complete tolerance was not obtained without achieving complete allergy resolution at each dose of the allergen before increasing the dosage in IFA. Both IFA and NFA can be successfully treated with OIT using IFN-gamma but show different clinical and therapeutic characteristics. IFN-gamma is necessary for the tolerance induction but not for tolerance maintenance. Additional study for the mechanisms of tolerance induction by IFN-gamma is needed.

The immune-modulatory effect of specific prebiotic oligosaccharides was shown in previous preclinical and clinical studies. To enhance the understanding of this effect, kinetic aspects of immune modulation and the correlation between microbiological and immunological parameters were investigated in a murine vaccination model. C57BL/6 mice were supplemented with short-chain galactooligosaccharides and long-chain fructooligosaccharides (ratio 9:1; Immunofortis()) in combination with pectin-derived acidic oligosaccharides. The timing of supplementation was varied around the primary (day 0) and secondary (day 21) vaccinations. Supplementation before the primary vaccination was necessary to increase delayed-type hypersensitivity responses (DTH) significantly at day 30. Supplementation after day 8 did not affect the DTH response at day 30, indicating that immune modulation occurred during the early phase. Therefore, correlation analysis of microbiological and immunological parameters was performed in a shortened experiment to focus on the early phase. At day 9 post-priming, the percentages of cecal lactobacilli were correlated to the DTH responses (p=0.01). Furthermore, the results suggested that yet unidentified factors may play a role. Additional analysis of intestinal Peyer's patch major lymphocyte populations did not show effects of supplementation. In conclusion, a specific oligosaccharide mixture was shown to exert its immune-modulatory effect during the early phase of a murine immune response. The results are consistent with a role of the microbiota and possibly other factors in oligosaccharide-induced immune modulation. Furthermore, the results demonstrate that it is critical to consider kinetic aspects of immune-modulatory and prebiotic effects in order to study their interaction in a meaningful way., (Copyright 2010 Elsevier B.V. All rights reserved.)

Darwinian fitness reflects trade-offs between reproduction and survival. Mechanisms have evolved in small nontropical mammals and birds to maximize reproductive output during the summer when thermoregulatory demands are relatively low and food is abundant and to shunt energy to processes that presumably increase the odds of survival during the winter when thermoregulatory demands are high and food is scarce. In order to predict the onset of winter, many seasonally-breeding mammals use day length (photoperiod) information. Seasonal adjustments of immune responses may be one mechanism to enhance survival; short days enhance cell-mediated immune function in seasonally-breeding rodents. The goal of the present study was to determine whether delayed-type hypersensitivity in hamsters is constrained or if photoperiod merely establishes a baseline level of immune response that can then be fined tuned by other environmental conditions. To test this, we used environmental enrichment, a manipulation that enhances many aspects of immune function. Hamsters were assigned to either long or short photoperiods and further assigned into either singly-housed or environmentally-enriched cages. After 10 weeks of concurrent photoperiod and housing treatment, delayed-type hypersensitivity (DTH) was induced. Although short days enhanced DTH responses compared with long days, environmental enrichment enhanced swelling responses in both short days and long days, suggesting that even during potential energetic bottlenecks or during maximal reproductive investment, hamsters can modulate their investment in immune function., ((c) 2010 Elsevier Inc. All rights reserved.)

Epstein-Barr virus-induced gene-3 (EBI-3) associates with p28 to form interleukin-27 (IL-27) or with IL-12p35 to form IL-35. Both IL-27 and IL-35 have immunosuppressive functions and especially IL-35 has been implicated in the suppressive function of regulatory T cells (Treg). To address the role of EBI-3 in immune regulation, delayed-type hypersensitivity (DTH) responses were examined in EBI-3-deficient (EBI-3(-/-)) mice. EBI-3(-/-) mice developed deteriorated DTH responses as shown by the enhanced footpad swelling and augmented infiltration of inflammatory cells into the antigen-challenged footpads as compared with wild-type (WT) mice. While EBI-3-deficiency showed little effects on antigen-specific IFN-gamma production of lymph node cells, IL-17 production was drastically augmented in EBI-3(-/-) cells as compared with in WT cells. In addition, reduced IL-10 production was also evident in EBI-3(-/-) CD4(+) T cells. Interestingly, the development and suppressive function of Treg to inhibit effector T cell proliferation was not affected by EBI-3-deficiency. These data clearly demonstrated the immunosuppressive function of EBI-3 and provided complementary evidence that EBI-3 and EBI-3-containing cytokines might be taken into consideration as potential targets for some immune-related diseases., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

The allergy-preventive activity of a 35% EtOH extract (IT) of flowers of Impatiens textori MIQ. was demonstrated in a continuing search for allergy-preventive substances from natural sources. The evaluation of its activity used an in vivo assay method for monitoring the blood flow decrease in the tail vein microcirculation of mice subjected to sensitization with hen-egg white lysozyme. Among the principal compounds in IT, apigenin (1), luteolin (3), and luteolin 7-glucoside (4) showed significant allergy-preventive effects.

Local anesthetics (LA) are common elicitors of adverse reactions and the clinical symptoms often correspond to anaphylaxis with tachycardia, hypotension and subjective feelings of weakness, heat or vertigo. The pathomechanism of immediate hypersensitivity reactions to LA is largely unknown -they are commonly regarded as 'pseudo-allergic' or 'non-immune type' anaphylaxis. Immunologically mediated reactions have rarely been observed with positive skin prick tests. Other ingredients in LA preparations have to be considered as elicitors, e.g. preservatives like benzoates or sulfites or latex contaminants in injection bottles. Practical management of patients with a history of LA reaction includes a careful allergy history, skin-prick and intradermal tests. Undiluted LA solutions may elicit false-positive intradermal test reactions. If prick and intradermal tests are negative, the procedure of subcutaneous provocation testing is applied in a placebo-controlled manner. When patients are constantly reacting to placebo, a regimen of 'reverse placebo provocation' with injection of a LA (verum) is applied while the patient is informed about receiving placebo in order to 'rule out psychosomatic involvement'. With this regimen it is possible to eliminate anxiousness and fear, and the patient has proof that he has tolerated the respective LA substance., (Copyright 2010 S. Karger AG, Basel.)

Purpose of Review: The purpose of the present review is to examine the hypersensitivity reactions to preservatives in topical ophthalmic therapies., Recent Findings: Ocular hypersensitivity reactions to different types of preservatives in different chemical classes of topical ophthalmic treatments reviewed in the literature include IgE-mast cell mediated, cell mediated and toxic. Quaternary ammoniums (benzalkonium chloride) are most commonly (8% reported cases in OVID and PubMED based searches) associated with irritant toxic reactions whereas the organomercurials (thimerosal) and the alcohols (chlorobutanol) have the highest association (19% of OVID and 14% of PubMED based searches and 20% of OVID and 11% of PubMED searches), respectively, with allergic responses although the term allergy for the 'alcohols' appears to be actually an irritant effect whereas the organomercurials appear to truly interact with the immune system as neoantigens., Summary: A large number of clinical and experimental studies reveal that preservatives in topical ophthalmic medications have been demonstrated to produce effects from inflammation/ hypersensitivity to permanent cytotoxic effects involving all structures of the eye.

Purpose of Review: A number of studies over recent years have shown the relevance of nonimmediate immunological reactions to drugs and emphasized the need for these reactions to be studied in greater depth, including both in-vivo and in-vitro tests and provocation studies., Recent Findings: Several clinical entities are involved, ranging from mild to severe reactions. Nonimmediate reactions have a special tropism for the skin, although other organspecific or systemic reactions may also occur. In the affected organ, the drug acts as a hapten or protohapten, originating an immunological stimulus that is followed by recruitment of T lymphocytes and other types of cells, depending on the reaction. This involves a trafficking phenomenon in which these cells use different receptors that interplay with their corresponding ligands in the tissue. In addition, a number of activation and cytotoxic markers are also expressed, which are related with disease severity., Summary: Current studies provide overwhelming evidence of the interaction between the organ involved, very often the skin, and immunocompetent cells. This is of relevance for diagnostic and therapeutic approaches.

Molecular and cellular assessment of dermal delayed-type hypersensitivity (DTH) responses is a useful approach for evaluating the mechanism of action (MOA) of immunomodulatory agents. In the present report, we characterized the delayed-type hypersensitivity response induced by keyhole limpet hemocyanin (KLH), and validated its utility by evaluating an immunomodulator, BIRB-796. Intradermal KLH challenge of the ear pinna following subcutaneous antigen sensitization resulted in a pronounced skin inflammation that peaked at 24-48h. At the molecular level, there was an activation of 3 mitogen-activated protein kinases (MAPKs: p38, JNK and ERK), an induction of the chemokines CCL2/JE, CXCL2/Mip-2, CXCL1/KC, CCL3/Mip-1alpha CCL4/Mip-1beta and CXCL10/IP-10, and expression of the cytokines IL-1beta and IL-10 in the ear parenchyma. Modulation of TNFalpha protein level was only detected in ex-vivo ear whole organ cultures (EWOC). Consistent with this inflammatory profile there was an infiltration of neutrophils and mononuclear cells into the ear parenchyma. BIRB-796, a potent allosteric p38 MAPK inhibitor attenuated the ear swelling response, which correlated with a reduced inflammatory profile. BIRB-796 inhibited p38 but not JNK or ERK kinase activation, decreased multiple chemokines which correlated with a decrease in the infiltration of neutrophils and macrophages; CD4 T cells were modesty reduced. Similarly, there was a decrease of levels of cytokines including IL-1beta, IL-10 and TNFalpha. These data support the utility of this model for evaluating immunomodulators on skin inflammation and suggest that modulation of p38 kinase may be of therapeutic value for the treatment of inflammatory skin conditions.

Itching erythematous or eczematous plaques around injection sites are quite frequent side effects of heparin treatment and clinical symptoms of delayed-type non-IgE-mediated allergic hypersensitivity (DTH) to heparin. For diagnosis, intradermal, patch, and subcutaneous challenge tests with heparins are suitable. In most cases, changing the subcutaneous therapy from unfractionated to low molecular weight heparin or treatment with heparinoids does not provide improvement because of extensive cross-reactivity. Hirudin polypeptides, which exhibit a different chemical structure, are a safe therapeutic alternative for subcutaneous application, however. Importantly, despite DTH to subcutaneously injected heparins, most patients tolerate heparin intravenously. Moreover, in case of therapeutic necessity and DTH to heparins, the simple shift from subcutaneous to intravenous heparin administration without prior testing may be justified.

Purpose of Review: This review presents the current knowledge of the role of T cells in drug allergy manifesting as exanthematous, pustular and bullous skin diseases, collectively referred to as nonimmediate allergic drug reactions., Recent Findings: Both CD4+ and CD8+ T cells producing type 1 and type 2 cytokines and endowed with cytotoxic properties are involved in nonimmediate allergic drug reactions. Recent studies have confirmed that CD8+ T cells play a major role in the pathophysiology of nonimmediate allergic drug reactions, and have characterized new cytotoxic molecular pathways responsible for the severity of the bullous forms of nonimmediate allergic drug reactions., Summary: Nonimmediate allergic drug reactions are mediated by T cells and mostly affect the skin. Nonimmediate allergic drug reactions comprise several diseases ranging from the frequent and benign maculo-papular exanthema to the severe and rare toxic epidermal necrolysis. Progress in the knowledge of the pathophysiology of nonimmediate allergic drug reactions comes from a better understanding of the mechanisms of drug recognition by T cells and from a careful analysis of the phenotype and functions of CD4+ and CD8+ T cells infiltrating the skin lesions. Recent studies have confirmed that the different clinical forms of nonimmediate allergic drug reactions are associated with distinct types of T cell-mediated skin inflammation. However, CD8+ T cells appear as major effector T cells in most of the nonimmediate allergic drug reactions. Future studies to analyze the early cellular and molecular events leading to the development of the allergic skin reaction will be helpful in order to define diagnostic and therapeutic targets.

Drug desensitization is the induction of temporary clinical unresponsiveness to drug antigens to which patients have presented severe hypersensitivity reactions. It is typically achieved by gradual reintroduction of small doses of drug antigens at fixed time intervals, and it is aimed at providing increased safety and protection from side effects, including anaphylaxis. Delivery of full therapeutic doses is achieved during desensitization, allowing patients to receive firstline chemotherapy, antibiotics, or monoclonal antibodies, as well as other drugs such as insulin, aspirin, and iron. Desensitizations are high-risk interventions. Inhibition of cellular activation mechanisms occurs during drug desensitization, allowing for the protective clinical outcomes and lack of side effects in the majority of cases, but the cellular and molecular inhibitory mechanisms are incompletely understood. The indication for desensitization protocols can only be done by trained allergists and immunologists and should be implemented as standard of care because of their high success rates and outcomes-demonstrated safety profile.

Contralateral orchitis induced by unilateral testicular injury has been reported as sympathetic orchitis in men and experimental animals. In mice, experimental sympathetic orchitis (ESO) was first demonstrated in the C3H/He strain after experimental testicular trauma. Delayed-typed hypersensitivity (DTH) to testicular germ cells is induced by testicular trauma and treatment with cyclophosphamide before the trauma further enhances anti-testicular germ cell DTH. In the present study we investigated ESO induction with or without cyclophosphamide pretreatment in two murine strains, C3H/He and A/J mice, that are susceptible to testicular autoimmunity. The results show that traumatized testes undergo early degeneration of the seminiferous epithelium followed by neutrophilic inflammation and later fibrosis with little lymphocytic infiltration, in both murine strains. In the contralateral testes, ESO characterized by both lymphocytic inflammation and spermatogenic disturbance was induced in both strains. However, the incidence and severity of ESO in A/J mice tended to be higher than in C3H/He mice. In contrast, cyclophosphamide pretreatment significantly augmented both pathological stages of ESO and anti-testicular germ cell DTH in C3H/He mice, while those in A/J mice were fully developed by testicular rupture alone and were not further augmented by cyclophosphamide pretreatment. We conclude that A/J mice are more sensitive to trauma-induced testicular autoimmunity than C3H/He mice.

T-helper (Th) 1/Th2 balance determines the direction of contact hypersensitivity (CHS). To clarify the immunopathogenesis of contact dermatitis, 2,4-dinitrofluorobenzene (DNFB)-induced CHS reaction was compared between the BALB/c and C57BL/6 mice. The two strains were sensitized with DNFB systemically and challenged with DNFB locally. The CHS reaction in BALB/c mice was intense compared with that in C57BL/6 mice at 24 and 48 hours post-DNFB challenge. The dermal lesions were characterized by infiltration of lymphocytes, eosinophils, neutrophils, and macrophages including CD4+ and CD8+ T cells, and interleukin (IL)-4-producing(+) and interferon (IFN)-gamma+ cells in BALB/c mice. In C57BL/6 mice, the composition of inflammatory cells was same as those in BALB/c mice except for eosinophils, CD4+ T cells, and IL-4+ cells. There was no increase in the number of mast cells in the two strains. Local and systemic productions of IL-4 and IFN-gamma in BALB/c mice were higher than those in C57BL/6 mice. Although blood IgE values increased in BALB/c mice, but not in C57BL/6 mice, at 48 hours postchallenge, its value was low. The delayed Th2-like response together with Th1-like response in BALB/c mice may induce strong CHS reaction compared with C57BL/6 mice, which may dominantly develop Th1-like reaction. Moreover, mast cell and IgE do not appear to be involved in delayed CHS.

Allergic rhinitis (AR) is the fifth most common chronic disease, and the association between allergic disorders and anxiety is well-documented. To investigate how anxiety and stressors modulate skin prick test (SPT) responses and associated inflammatory responses, 28 men and women with AR were selected by clinical history and skin test responses. The participants were admitted twice to a hospital research unit for 4h in a crossover trial. Changes in SPT wheals were assessed before and after a standardized laboratory speech stressor, as well as again the following morning; skin responses assessed twice during a lab session without a stressor and again the following morning served as the contrast condition. Anxiety heightened the magnitude of allergen-induced wheals following the stressor. As anxiety increased, SPT wheal diameters increased after the stressor, compared to a slight decrease following the control task. Anxiety also substantially enhanced the effects of stress on late phase responses: even skin tests performed the day after the stressor reflected the continuing impact of the speech stressor among the more anxious participants. Greater anxiety was associated with more IL-6 production by Con A-stimulated leukocytes following the stressor compared to the control visit. The data suggest that stress and anxiety can enhance and prolong AR symptoms.

In the present study, we used the electronic version of the von Frey test to investigate the role of cytokines (TNF-alpha and IL-1beta) and chemokines (KC/CXCL-1) in the genesis of mechanical hypernociception during antigen-induced inflammation in mice. The nociceptive test consisted of evoking a hindpaw flexion reflex with a hand-held force transducer (electronic anesthesiometer) adapted with a 0.5 mm(2) polypropylene tip. The intraplantar administration of methylated bovine serum albumin (mBSA) in previously immunized (IM), but not in sham-immunized (SI) mice, induced mechanical hypernociception in a dose-dependent manner. Hypernociception induced by antigen was reduced in animals pretreated with IL-1ra and reparixin (a non-competitive allosteric inhibitor of CXCR2), and in TNF receptor type 1 deficient (TNFR1-/-) mice. Consistently, antigen challenge induced a time-dependent release of TNF-alpha, IL-1beta and KC/CXCL-1 in IM, but not in SI, mice. The increase in TNF-alpha levels preceded the increase in IL-1beta and KC/CXCL1. Antigen-induced release of IL-1beta and KC/CXCL1 was reduced in TNFR1-/- mice, and TNF-alpha-induced hypernociception was inhibited by IL-1ra and reparixin. Hypernociception induced by IL-1beta in immunized mice was inhibited by indomethacin, whereas KC/CXCL1-induced hypernociception was inhibited by indomethacin and guanethidine. Antigen-induced hypernociception was reduced by indomethacin and guanethidine and abolished by the two drugs combined. Together, these results suggest that inflammation associated with an adaptive immune response induces hypernociception that is mediated by an initial release of TNF-alpha, which triggers the subsequent release of IL-1beta and KC/CXCL1. The latter cytokines in turn stimulate the release of the direct-acting final mediators, prostanoids and sympathetic amines.

Background: beta-Lactam (BL) antibiotics can induce non-immediate skin reactions, frequently manifested as exanthema or urticaria. The time between drug intake and the reaction appearance is generally 24-48 h. Because the mechanisms involved are not completely understood, diagnostic tests for these reactions have still to be fully validated., Objective: To evaluate the role of skin and drug provocation tests (DPTs) in the diagnosis of patients with non-immediate reactions to BL., Methods: We evaluated a group of 22 patients who developed maculopapular exanthema or urticarial exanthema after BL intake. Diagnosis was confirmed by DPT with BL. Intradermal/patch testing was performed with benzylpenicilloyl, minor determinant mixture, amoxicillin (AX), ampicillin (AMP) and the culprit drug in patients and in 22 negative controls. Immunohistochemical studies were done in the affected skin at the acute phase of the reaction and after a delayed positive skin test/DPT. IFN-gamma and IL-4 were quantified in peripheral mononuclear cells, obtained during the positive response to DPT and after resolution of the symptoms., Results: From the total number of cases, 12 patients developed urticarial exanthema and 10 maculopapular exanthema after DPT. Only two of the 22 patients (9%) had a positive delayed intradermal skin test: one to AX/AMP and the other to cloxacillin. Biopsies showed a mononuclear CD4, CD8 infiltrate and activated and memory cells. The cytokine expression showed a Th1 pattern in patients, in contrast with the Th0 pattern in controls., Conclusion: In patients with non-immediate reactions to BLs (maculopapular exathema or urticarial exanthema), the sensitivity of skin testing is low and DPT may be required to establish the diagnosis. The reproducibility of the reactions and the cytokine pattern expressed during the acute episode support a T cell-induced non-immediate response.

Background and Purpose: Our aim was to examine the effect of demethylnobiletin on various experimental models of delayed-type hypersensitivity (DTH) reactions and to determine its influence on the mediators and enzymes involved in these reactions., Experimental Approach: DTH was induced in mice by oxazolone, dinitrofluorobenzene (DNFB) and sheep red blood cells (SRBC). The effect of demethylnobiletin on the ensuing DTH was studied, especially in relation to oedema formation, cell infiltration and tissue damage. Its activity on different mediators implicated in DTH reactions was also determined and its effect on nitric oxide synthase (NOS)-2 analysed. Finally, its influence on T lymphocyte proliferation, apoptosis and caspase 3 activity was tested., Key Results: DTH reactions were all reduced by demethylnobiletin. The experimental results suggest that the compound may act by reducing cell infiltration and by suppressing mediators such as interleukin-2 (IC50=1.63 microM), interleukin-4 (IC50=2.76 microM), tumour necrosis factor-alpha (IC50=0.66 microM), interferon-gamma (IC50=1.35 microM), and interleukin-1 beta (46% at 2.5 microM) and by concomitantly increasing the production of the anti-inflammatory cytokine, interleukin-10. In addition, while demethylnobiletin affected nitric oxide production, it did not modify NOS-2 expression. Finally, demethylnobiletin inhibited proliferation of T cells and induced their apoptosis., Conclusions and Implications: Demethylnobiletin decreased DTH reactions induced by various agents. This finding, along with the fact that the compound has a low toxicity and exhibits several other interesting properties, could pave the way for other structurally related citroflavonoids to be used as pharmacological agents in complementary therapies.

Type IV of hypersensitivity reaction is usually manifested in the skin in different clinical pattern. According to traditional Gell and Coombs classification, the mechanism of IV type of allergic reaction has been associated with contact allergy with the activity of lymphocytes Th1 secreting interferon gamma. Now, this vision seems to be too simplified. In the last years there were publications, which can throw a new light on these complicated mechanisms leading to the development of the type IV of allergy, especially to drugs, nickel and other haptens and also can explain the differentiation of clinical pattern in respective patients. The skin symptoms in type IV of hypersensitivity are triggered by activation of specific T-cell CD4+ and CD8+. Immunohistochemical and functional analysis of reactive T-cell has shown that the delayed hypersensitivity reaction depends on the secreted cytokines. For example maculo-papular exanthema may be either triggered by Th1 or Th2 in nature and cytokines interferon gamma, tumor necrosis factor alfa or interleukin-4, 5 and 13. Bullous reactions (i.e. Stevens-Johnsons Syndrome or toxic epidermal necrolysis) are characterized by widespread keratinocyte apoptosis, a consequence of high CD8+ T-cell involvement and the molecular cytotoxicity of Fas, perforin and granzyme B. Pustular exanthema reactions are stimulated via the T-cell release of 11-8 and granulocyte-monocyte colony-stimulatig factor (GM-CSF). For the better understanding of these inflammatory cascades deleted type IV of hypersensitivity reactions have been re-classified into four main subtypes: 1. IVa with Th1 and monocyte directed and cytokines: IFNgamma, IL-1, IL-2, 2. IVb with Th2 and eosinophils directed and cytokines: L-5, IL-4, IL-13, 3. IVc with T CD8+ directed and cytokines: perforin, granzyme B, Fas Ligand, 4. IVd with T CD4+, CD8+ and neutrophil directed and cytokines: IL8, GM-CSF. Clinically delayed hypersensitivity eruptions are often an overlap of cytokine pathways, with one preferential reaction dominating the final picture. Type IVa and IVc play a role inthe mechanism of contact dermatitis, however type IV b in chronic asthma, chronic allergic rhinitis and maculo-papular exanthema with eosinophilia, type IV c in bullous reactions (i.e. Stevens-Johnsons Syndrome or toxic epidermal necrolysis), so type IV d in pustular exanthema reactions (i.g. AGEP - Acute Generalized Exanthematosus Pustule, Behcet disease). This different clinical pattern of allergic disease mainly including drug allergy to nickel and other haptens as well as chronic asthma and allergic rhinitis may be explained by above mechanisms. The study of different mechanisms of four subtypes of type IVof allergic reaction may be helpful in the differential diagnostics and in the treatment of allergic diseases.

The effects of two major forms of prolactin (PRL) were examined on delayed type hypersensitivity (DTH) responses to Candida albicans. Unmodified PRL (U-PRL) had no effect on the DTH response, whereas a molecular mimic of phosphorylated PRL (S179D PRL) significantly inhibited immune responses to this robust antigen. This effect of S179D PRL was not accompanied by gross alterations in splenic T cell numbers, CD4/CD8 ratios, or T and B cell activation markers, but did produce a decrease in splenocyte apoptosis. Using gld animals, Fas ligand (FasL) was implicated in the suppressive effects of S179D PRL. Circulating IgG1 and IgG2 antibody levels were increased in response to treatment with both forms of PRL, but the effects of S179D PRL were most pronounced. Cytokine changes in the popliteal lymph nodes specific to S179D PRL treatment showed an inhibition of pro-inflammatory cytokines. In conclusion, mice treated with a molecular mimic of phosphorylated prolactin showed a profound inhibition of DTH responses to Candida correlating with an absence of GM-CSF, IL-4, and IL-13 production and a marked reduction in IL-12p70 synthesis.