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Although acute stress generally exerts positive effects on the immune system, chronic stress typically causes immunosuppression via the hypothalamic–pituitary–adrenal (HPA) axis. In this study, the effects of capsaicin (1.28 mg/kg intraperitoneally [i.p.] for 7 days) on immune parameters were evaluated under conditions of chronic stress. Capsaicin treatment significantly increased the immune response as evaluated by the delayed-type hypersensitivity (DTH) reaction to dinitrofluorobenzene (DNFB) and splenocyte proliferation assays- It also is able to rescue the splenocytes of the apoptosis induced by stress. The capsaicin treatment increased the production of Th1 cytokines and decreased the production of Th2 cytokines and TGF-β1 in the plasma and culture supernatants of immunosuppressed mice, which is associated with the modulation of Th2 induced by stress cells. Moreover, the production of corticosterone significantly decreased in capsaicin-treated animals as compared to control groups. The capsaicin treatment further attenuated the immunosuppression induced by the corticosterone treatment (40 mg/kg i.p. for 7 days), albeit less potently, as exhibited in the DTH response. Intriguingly, the capsaicin treatment decreased the induction of IL-10, IL-4, and TGF-β1 through high doses of corticosterone, indicating direct cellular immunomodulation. These results show, that capsaicin is able to modulate chronic stress-induced immunosuppression, mediating corticosterone released inhibition, but also, that capsaicin significantly modulates the pharmacological action of corticosterone in vivo.

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound

As the primary defense against pathogens, the immune system uses numerous strategies to ensure optimal protection for the host. When immune responses go awry, however, they can cause great damage. “Hypersensitivity” is a broad term used to describe an excessive and/or pathogenic immune response to either foreign or self antigens. Gell and Coombs were the first to categorize hypersensitivity reactions into 4 types according to pathophysiology, but more recent insights into the mechanisms of these disorders have since modified the original classification system. This review describes the immune mechanisms involved in each of the modern Gell-Coombs categories.

Summary Clindamycin is widely used in the prophylaxis and treatment of infections due to its broad spectrum of antimicrobial activity. Hypersensitivity to clindamycin seems to be not very common (less than 1% of drug-allergic reactions) and it mostly appears as delayed T-cell mediated. For the diagnosis, skin testing is considered to be highly sensitive and rather safe, but cutaneous and systemic reactions have been described. Provocation test is considered the gold standard. However, it includes the possibility of severe reactions. We reported two cases of delayed allergic reaction to clindamycin, confirmed with a positive lymphocyte transformation test, showing this in vitro test like a promising diagnostic method because of its usefulness and safety.

Delayed type hypersensitivity (DTH) reactions are considered infrequent complications in arthroplasty, but have been recognized to be associated with devastating morbidity and substantial decrease in quality of life of affected patients. Chronic inflammation of artificial joints and associated loss of peri-implant bone often require revision surgery. Methods for the diagnosis of implant-related DTH are available but infrequently considered to the full extent. Sequential diagnostics based on exclusion of septic complications, local and systemic metal level determination, lymphocyte transformation testing (LTT), and local T cell subset analysis are required for an unequivocal DTH diagnosis. Here, we report on a patient with a history of chronic rheumatoid arthritis and an unfavorable outcome of unilateral knee arthroplasty. This case illustrates pitfalls and difficulties in the course of recurrent inflammation following joint replacement. In the early course, suspicion of low-grade bacterial infection led to three two-stage revisions. Afterwards, the joint was proven to be sterile. However, metal level quantification revealed release of especially cobalt and chromium from the joint, LTT indicated persisting cobalt and nickel sensitization and subset analysis of T cells from the synovium suggested DTH as a root cause for the inflammatory symptoms. This report aims to recommend the depicted diagnostic algorithm as an adequate tool for future DTH detection. Yet, systemic to local subset ratios for effector memory and regulatory T cells should be derived from sufficient patient numbers to establish it as a diagnostic marker. Moreover, future prospects regarding implant-related DTH diagnostics are discussed. Therapeutic options for the portrayed patient are proposed, considering pharmaceutical, cell-therapeutic and surgical aspects. Patients who experience peri-implant inflammation but do not have obvious mechanical or infectious problems remain a diagnostic challenge and are at high risk of being treated inadequately. Since potentially sensitizing materials are regularly used in arthroplasty, it is essential to detect cases of acute DTH-derived inflammation of an artificial joint at early postoperative stages. This would reduce the severity of inflammation-related long-term consequences for affected patients and may avoid unnecessary revision surgery.

The persistence of new leprosy cases in endemic areas such as India, Brazil, Bangladesh, and the Philippines has encouraged studies of chemoprophylaxis among contacts of patients. Epidemiological screening tools to enable early detection of infected individuals in endemic populations would be critical to target individuals most in need of intervention. Despite decades of attempts, however, there still are no tests available for the early detection of low-level infection with Mycobacterium leprae. In this report, we describe the development of a leprosy skin test using M. leprae-specific antigens. We selected the chimeric LID-1 fusion protein, formulated to achieve maximum performance at a minimal dose, as a skin test candidate based on its ability to elicit delayed-type hypersensitivity (DTH) reactions in M. leprae immune guinea pigs in a sensitive and specific manner, i.e., with no cross-reactivity observed with other mycobacterial species. Importantly, evaluations in armadillos indicated that intradermal inoculation of formulated LID-1 could distinguish uninfected from M. leprae-infected animals manifesting with symptoms distinctly similar to the PB presentation of patients. Together, our data provide strong proof-of-concept for developing an antigen-specific skin test to detect low-level M. leprae infection. Such a test could, when applied with appropriate use of chemo- and/or immunoprophylaxis, be instrumental in altering the evolution of clinical disease and M. leprae transmission, thus furthering the objective of zero leprosy.

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Penicillin allergy, local anesthetic hypersensitivity, latex allergy, contact hypersensitivity, and anaphylaxis are among the allergic reactions encountered in dental practice. This article reviews the literature pertaining to these important areas of overlap between dentistry and allergy/immunology. The epidemiology, diagnosis, and management of penicillin allergy as it relates to dentistry are reviewed. The relevant literature regarding local anesthetic and latex hypersensitivity is discussed. In addition, the presentation, evaluation, and management of contact hypersensitivity, including that to metals, are addressed. Recognition and appropriate treatment of anaphylaxis also are reviewed. This article will help dentists understand potential areas of comanagement with allergists/immunologists to optimize patient care.

T cells chronically stimulated with the same peptide tend to express exhaustion markers such as PD-1 or LAG-3. Deficiencies in the PD-1 and LAG-3 pathways have been linked to the development of autoimmune diseases. IMP761 is a LAG-3–specific humanized agonist Ab with immunosuppressive properties both in vitro and in vivo in an Ag-specific delayed-type hypersensitivity (DTH) model in the cynomolgus macaque (Macaca fascicularis). IMP761 inhibits TCR-mediated NFAT activation and Ag-induced human T cell proliferation and activation. In the DTH model, assessment of T cell infiltration and gene expression profile at the DTH biopsy site corresponds to immunosuppression of an Ag-induced T cell response. IMP761 is the first LAG-3–specific agonist product candidate, acting upstream on activated T cells, the root cause of self-Ag–specific T cell–induced autoimmune diseases.

Acute interstitial nephritis (AIN) is a rare, often underdiagnosed condition and a common cause of renal failure. Drugs are the leading cause. The underlying pathophysiological condition is often a type IV hypersensitivity reaction. There are also rarer idiopathic forms, which often remain unrecognized. Additionally, the pathophysiological mechanisms are poorly understood, so that only very few promising forms of treatment are available. For some medications the overall risk is low but the side effects are relevant for the clinical routine due to the fact that they are frequently prescribed. In addition, the development of new approaches, such as immunotherapy also leads to side effects that cannot be completely predicted. For many diseases the occurrence of acute kidney injury increases the mortality and morbidity. A potentially irreversible chronic renal failure increases the incidence of further comorbidities and reduces the quality of life. Treatment is difficult and mostly empirical.

Natural rubber latex (NRL) is a frequent cause of immediate type I hypersensitivity, but delayed type IV reactions can also occur.

Sea urchin injuries (SUIs) are among the most common marine injuries; however, there are no guidelines to dictate appropriate workup and treatment. Complications vary significantly depending on the extent of injury, site of injury and elapsed time to medical attention. Timely and appropriate management can prevent long-term morbidity despite the deceptively innocuous appearance of these injuries. We review the English literature on SUIs and offer an algorithm to aid in the management of affected patients. We found that superficially retained spines may trigger a local granulomatous inflammatory response, while spines retained near deep structures may induce sea urchin arthritis, inflammatory tenosynovitis, among other delayed complications. Therefore, we recommend immediate inactivation of pro-inflammatory compounds by hot water soaks at the time of injury, followed by extraction of all spines by a physician. Imaging is a valuable component of risk stratification to determine depth and location of spines, which guides selection of appropriate extraction technique to prevent long-term morbidity.

The vector-borne disease leishmaniasis is transmitted to humans by infected female sand flies, which transmits Leishmania parasites together with saliva during blood feeding. In Iran, cutaneous leishmaniasis (CL) is caused by Leishmania (L.) major and L. tropica, and their main vectors are Phlebotomus (Ph.) papatasi and Ph. sergenti, respectively. Previous studies have demonstrated that mice immunized with the salivary gland homogenate (SGH) of Ph. papatasi or subjected to bites from uninfected sand flies are protected against L. major infection.In this work we tested the immune response in BALB/c mice to 14 different plasmids coding for the most abundant salivary proteins of Ph. sergenti. The plasmid coding for the salivary protein PsSP9 induced a DTH response in the presence of a significant increase of IFN-γ expression in draining lymph nodes (dLN) as compared to control plasmid and no detectable PsSP9 antibody response. Animals immunized with whole Ph. sergenti SGH developed only a saliva-specific antibody response and no DTH response. Mice immunized with whole Ph. sergenti saliva and challenged intradermally with L. tropica plus Ph. sergenti SGH in their ears, exhibited no protective effect. In contrast, PsSP9-immunized mice showed protection against L. tropica infection resulting in a reduction in nodule size, disease burden and parasite burden compared to controls. Two months post infection, protection was associated with a significant increase in the ratio of IFN-γ to IL-5 expression in the dLN compared to controls.This study demonstrates that while immunity to the whole Ph. sergenti saliva does not induce a protective response against cutaneous leishmaniasis in BALB/c mice, PsSP9, a member of the PpSP15 family of Ph. sergenti salivary proteins, provides protection against L. tropica infection. These results suggest that this family of proteins in Ph. sergenti, Ph. duboscqi and Ph. papatasi may have similar immunogenic and protective properties against different Leishmania species. Indeed, this anti-saliva immunity may act as an adjuvant to accelerate the cell-mediated immune response to co-administered Leishmania antigens, or even cause the activation of infected macrophages to remove parasites more efficiently. These findings highlight the idea of applying arthropod saliva components in vaccination approaches for diseases caused by vector-borne pathogens.

Lenalidomide is an immunomodulatory agent that belongs to a family of IMiDs used to treat multiple myeloma. Hypersensitivity and skin reactions are adverse effects of lenalidomide that may lead to discontinuation of its use for multiple myeloma making them contraindicated to other IMiD therapies. Desensitization protocols have been developed to desensitize patients to lenalidomide skin reaction and rash. We report a case series of 5 patients undergoing slow lenalidomide desensitization protocol in an outpatient cancer center setting. Four of the five patients were able to be successfully desensitized to lenalidomide. We also demonstrate safety of using slow lenalidomide desensitization while on combination therapy for control of multiple myeloma.

International audience; There is no perfect agreement on how to perform an allergy workup in suspected beta-lactam (BL)-allergic children, since skin test (ST)-induced pain is often a limitation. The aim of the study was to assess the possibility of reducing the number of ST in children when performing a complete allergy workup for BL hypersensitivity reactions.Methods: A retrospective analysis of all patients referring to the Allergy Unit of the University Hospital of Montpellier (France) with positive responses in immediateand non-immediate-reading ST to a BL over a 16-year period was performed, to determine the positive predictive value (PPV) of ST. All pediatric patients with a suspected BL hypersensitivity were skin-tested with the suspected drug only, during the following 54 months.Results: A total of 319 patients reporting 328 BL reactions were included in the retrospective study. The PPV of ST for the reported drug was of 99.4%. Based on the results, the number of patients to include in the prospective study was estimated to be 101. In the prospective study, 229 children were included. We diagnosed a BL hypersensitivity in 12 children (5.2%): Diagnosis was reached in 6 (50.0%) through ST (delayed reading for all) and in 6 through drug provocation test (DPT).Conclusion: ST with BL should therefore be performed as a screening test, before DPT, and testing only the suspected drug may be sufficient when dealing with children.

The aim of this work was to study effects of ketotifen fumarate (KF) on prevention of tissue damage in testes of rats with experimental autoimmune orchitis (EAO) and on the contralateral testis in a model of prolonged testicular cord torsion (TCT). Rats with EAO or TCT were injected intraperitoneally once daily with KF or saline solution (vehicle group). Incidence and severity of testicular damage were evaluated by histopathology using an EAO score or a Johnsen score. Mast cells (MC) were identified by histochemistry and quantified. In EAO model, KF significantly reduced severity of histopathological testicular damage compared to rats in the vehicle group. KF also reduced the number of testicular MC compared to vehicle group. Similarly, in TCT model, multifocal damage of the contralateral testis was observed 30 days after testicular torsion characterized by sloughing of the germinal epithelium, seminiferous tubule atrophy, and interstitial edema. Focal signs of inflammation and fibrosis of seminiferous tubular walls were also observed. In contrast, sections of contralateral testis of rats injected with KF and killed 30 days after surgery showed normal histological features. A significant decrease in the number of MC was observed in rats treated with KF compared to untreated animals. In conclusion, we demonstrated that treatment with KF reduced testicular inflammatory process and MC infiltrates in both EAO and TCT models. The results suggest a promising treatment for infertile male patients with testicular pathologies associated with inflammation and germ cell loss. Fil: Moreno, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Sobarzo, Cristian Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Lustig, Livia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Rodriguez Peña, Marcelo Javier. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Campo de Mayo Cirujano Primero Doctor Juan Madera; Argentina Fil: Guazzone, Vanesa Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina

Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic resistance are widespread, and algorithms to clarify β-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers but also in understanding the effect on quality of life and developing better treatments has been made for patients with chronic idiopathic urticaria. Patients with hereditary angioedema (HAE) have gained additional access to highly efficacious therapies, with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal laboratory results. Guidelines have defined clear goals to help providers optimize therapies in patients with HAE. The epidemiology and triggers of anaphylaxis and the mechanisms underlying anaphylaxis were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individual persons and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in patients with drug allergy, urticaria, HAE, and anaphylaxis.

OBJECTIVE: Toreview published studies on galactose α-1,3-galactose (α-gal), a carbohydrate epitope found on proteins and lipids in nonprimate mammals and present in foods (particularly organ or fat-rich red meat) and medications, where it causes delayed-onset and immediate-onset anaphylaxis. DATA SOURCES: A literature search for the terms galactose α-1,3-galactose and α-gal using PubMed and Embase was performed. STUDY SELECTIONS: Studies on α-gal were included in this review. RESULTS: Several species of ticks contain α-gal epitopes and possibly salivary adjuvants that promote high titer sensitization and clinical reactivity. Risk factors for α-gal syndrome include exposure to ticks of particular species. Age and sex differences seen in various cohorts possibly reflect the prevalence of these exposures that vary according to setting. CONCLUSION: The reason and mechanisms for delayed onset of food-related anaphylaxis and the preponderance of abdominal reactions are not clear but may involve the kinetics of allergen digestion and processing or immunologic presentation via a different mechanism from usual immediate-type food allergy.

The α-Gal syndrome is a tick-associated and emerging IgE-mediated hypersensitivity reaction directed against the carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) epitope after red meat intake. Herein, we describe a clinical case of a 44-year-old French patient who suffered from recurrent anaphylactic reactions after mammalian meat consumption for five years before the final diagnosis of the α-Gal syndrome was established in 2018. The patient also reported multiple tick bites prior to symptom onset. This unique type of allergy has increasingly been reported across the world, but it is still unknown in many European countries. Therefore, the present clinical case should increase awareness among primary care practitioners and further improve the early diagnosis of the α-Gal syndrome in affected individuals., El síndrome de α-Gal es una reacción de hipersensibilidad mediada por IgE emergente y asociada a garrapatas dirigida contra el epítopo de carbohidratos Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) después de la ingesta de carne roja. En este documento, describimos un caso clínico de un paciente francés de 44 años que sufrió reacciones anafilácticas recurrentes después del consumo de carne de mamífero durante cinco años antes de que se estableciera el diagnóstico final del síndrome α-Gal en 2018. El paciente también informó múltiples garrapatas. muerdeantes del inicio de los síntomas. Este tipo único de alergia se ha informado cada vez más en todo el mundo, pero aún se desconoce en muchos países europeos. Por lo tanto, el presente caso clínico debería aumentar la conciencia entre los médicos de atención primaria y mejorar aún más el diagnóstico precoz del síndrome de α-Gal en las personas afectadas.

The study aimed to investigate the immunomodulatory activity of oligopeptides derived from oat (Avena nuda L.) (OOPs). Healthy female BALB/c mice were randomly assigned to five groups, given deionized water (control) and 0.25, 0.5, 1.0, and 2.0 g/kg body weight (BW) of OOPs daily by intragastric administration. Seven assays were performed to determine the immunomodulatory effects of OOPs on immune organ ratios, cellular and humoral immune responses, macrophage phagocytosis, and natural killer (NK) cell activity. Spleen T lymphocyte subpopulations (by flow cytometry), serum cytokine and immunoglobulin levels (by multiplex sandwich immunoassays) were determined to evaluate how OOPs affected the immune system. Our results showed that OOPs could significantly improve innate and adaptive immune responses in mice through the enhancement of cell-mediated and humoral immunity, macrophage phagocytosis capacity, and NK cell activity. We concluded that the immunomodulatory effects might be attributed to increased T and Th cell percentages, serum interferon (IFN)-γ, interleukin (IL)-1 α, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)- α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretions as well as immunoglobulin (Ig) A, IgG, and IgM productions. These results indicate that dietary OOPs could be considered as promising immunomodulators with dosages ranging from 0.25 to 2.0 g/kg BW.

Delayed anaphylaxis to mammalian meat is a newly recognized IgE-mediated syndrome associated with Lone Star tick bites. IgE-mediated anaphylaxis classically occurs within one hour of exposure to the allergen, which is typically a protein epitope. However, in this disease, circulating antibodies to a carbohydrate, alpha-gal (galactose-alpha-1,3-galactose), stimulate the anaphylactic cascade with hives, diarrhea, abdominal cramps, respiratory distress and anaphylactic shock developing after ingestion of beef, pork or lamb meat. The delayed onset of symptoms three to six hours after ingestion of meat is unique. Recognition and understanding of this disease is important for treating and educating patients with suggestive symptoms. Avoidance of red meat is the recommended therapy.

A 32-year-old pregnant woman (G5P0L0A4) presented at 10+ weeks of gestation with multiple itchy plaques of 3 weeks duration. She was a known case of antiphospholipid antibody syndrome and was on treatment with low molecular weight heparin (LMWH, enoxaparin) and aspirin since past 4 weeks. On examination, multiple erythematous, indurated plaques were present on the abdomen (figure 1A) and both upper thighs. The lesions were restricted to the sites of subcutaneous enoxaparin injections. Histopathology of the …

There is an increasing demand for alternative in vitro methods to replace animal testing, and, to succeed, new methods are required to be at least as accurate as existing in vivo tests. However, skin sensitization is a complex process requiring coordinated and tightly regulated interactions between a variety of cells and molecules. Consequently, there is considerable difficulty in reproducing this level of biological complexity in vitro, and as a result the development of non-animal methods has posed a major challenge. However, with the use of a relevant biological system, the high information content of whole genome expression, and comprehensive bioinformatics, assays for most complex biological processes can be achieved. We propose that the Genomic Allergen Rapid Detection (GARD™) assay, developed to create a holistic data-driven in vitro model with high informational content, could be such an example. Based on the genomic expression of a mature human dendritic cell line and state-of-the-art machine learning techniques, GARD™ can today accurately predict skin sensitizers and correctly categorize skin sensitizing potency. Consequently, by utilizing advanced processing tools in combination with high information genomic or proteomic data, we can take the next step toward alternative methods with the same predictive accuracy as today’s in vivo methods—and beyond.

Summary Background. Different clinical pictures are related to corticosteroids (CS) non immediate hypersensitivity and the frequency of these reactions can be underestimated. The classification of CS in 3 groups and the identification of two patient's profiles has been proposed by Baeck to help clinicians in the management of these cases. Methods. Data of 14 patients with clinical history of delayed reactions to various CS and positive skin test and/or oral challenge are retrospectively analyzed. Results. Three different patterns of patients are identified evaluating history, clinical picture and tests results. The first one (6 pts, 43%) is characterized by cutaneous and/or mucosal reaction due to inhaled Budesonide and patch test positive only to topical molecules belonging to the group 1 of CS. The second pattern (4 pts) has clinical history of local and systemic skin reactions to the topic and parenteral administration of the same or other steroid drugs. Patients belonging to the third pattern (4 pts) have a history of systemic reactions to general administration of CS without previous contact reaction. Pattern 2 and 3 show a wide sensitization to molecules belonging to the 3 groups of CS. All the patients show patch test positive to Budesonide. Conclusions. Although the lack of standardization, the allergy workup proves useful to differentiate patients sensitized to one or few molecules from polysensitized and to identify the culprit drugs. Intradermal and challenge test are necessary to complete the diagnostic workup. The results suggest the possibility of a different management of patients. Patients of pattern one can be only patch tested with a limited series of CS belonging to the 3 groups. They don't need an extensive exclusion of steroids use. The pattern 2 and 3 must be submitted instead to a complete allergological individual evaluation to identify alternative tolerated drugs, because of the risk of systemic reactions. The Baeck's classification shows limited usefulness in these cases.

Objective To understand the anti-virus adaptive immune response occurring during SARS-Cov-2 infection is necessary to have methods to investigate cellular and humoral components. The goal of this study has been to investigate the utility of a specific spike-DTH test using a coronavirus recombinant protein in COVID-19 patients. Methods DTH studies were performed by intradermal injection of a commercial recombinant spike protein from SARS-CoV-2 along with conventional serology studies. Results Fifty-one COVID-19 patients were studied showing 84,3% of concordance with spike-DTH and anti-RBD-IgG. Spike-DTH was superior to identify seven more COVID-19 individuals. A high specificity was found with no positive spike DTH reactions in the non-sick individuals. The skin test also showed more stable results over time while specific anti-RBD-IgG decreased gradually. Clinical severity groups also showed a progressive gradient of larger positive spike-DTH. Conclusion Specific spike DTH test seems to be an easy method to study cell immune response.

Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracellular vesicles (EVs) secreted by MSCs (EVMSC) are able to recapitulate the immunosuppressive properties of parental cells. As a next step, clinical trials to corroborate preclinical studies should be performed. However, effective dose in large mammals, including humans, is quite high and EVs industrial production is hindered by the proliferative senescence that affects MSCs during massive cell expansion. We generated a genetically modified MSC cell line overexpressing hypoxia-inducible factor 1-alpha and telomerase to increase the therapeutic potency of EVMSC and facilitate their large-scale production. We also developed a cytokine-based preconditioning culture medium to prime the immunomodulatory response of secreted EVs (EVMSC-T-HIFc). We tested the efficacy of this system in vitro and in a delayed-type hypersensitivity mouse model. MSC-T with an HIF-1α-GFP lentiviral vector (MSC-T-HIF) can be effectively expanded to obtain large amounts of EVs without major changes in cell phenotype and EVs composition. EVMSC-T-HIFc suppressed the proliferation of activated T-cells more effectively than did EVs from unmodified MSC in vitro, and significantly blunted the ear-swelling response in vivo by inhibiting cell infiltration and improving tissue integrity. We have developed a long-lived EV source that secretes high quantities of immunosuppressive EVs, facilitating a more standard and cost-effective therapeutic product.

Beta-lactam (BL) antibiotics are the most frequent cause of drug hypersensitivity in children, inducing both immediate and non-immediate reactions. Here we report a case of a 4-year-old child with a disseminated maculopapular exanthema 7 days after the first dose of amoxicillin–clavulanate, referred to our paediatric allergy department. Skin prick tests were negative. Intradermal tests were performed and, after 10 hours, indurated wheals larger than 10×10 mm with progressive erythema and disseminated maculopapular eruption were developed, related to amoxicillin and amoxicillin–clavulanate. Systemic reactions to BL skin tests are rarely reported and the majority are immediate reactions. This case illustrates a rare example of a non-immediate systemic reaction to intradermal tests, underlying the importance of skin testing before drug provocation tests in cases of moderate to severe non-immediate reactions.

Ethnopharmacological relevance Jianqu, a classical formula of traditional Chinese medicine, is used clinically to treat symptoms like chill and fever headache, diarrhea and loss of appetite and act on patients with low immunity. However, the quality control of Jianqu fermentation is not well established, and its function in regulating the body's immunity still remains unclear. Aim of the study The present study firstly assesses the structure and diversity of fungal community during Jianqu fermentation and then investigates the immune regulating function of Jianqu extract in mouse model. Materials and method The high-throughput sequencing is conducted to analyze the diversity and distribution of fungal community during the fermentation process of Jianqu, and then fungi with a high frequency and relative abundance are isolated. The immunosuppressed mice are induced by using cyclophosphamide (CTX) and used to evaluate the immune regulating function of Jianqu extract from natural fermentation or directed fermentation, respectively. Results With the fermentation, the diversity and distribution of fungal community significantly changed. The number of OTU (operational taxonomic unit) was gradually decreased from 223 ± 1 in the early phase to 201 ± 11 in the middle phase and to 175 ± 32 in the later phase of Jianqu fermentation. Generally, in genus level, Millerozyma, Debaryomyces and Rhizomucor showed a significant increase and became dominant in the mid or later phase of fermentation, while the Aspergillus displayed a decrease following the fermentation. However, Saccharomycopsis is a dominate species in surveyed samples. Next, six fungi strains with a high frequency and relative abundance, including Saccharomycopsis fibuligera, Millerozyma farinose, Hyphopichia burtonii, Rhizomucor pusillus, Lichtheimia ramosa, and Monascus purpureus, are isolated successfully. Interestingly, directed fermentation for Jianqu with the six isolated fungi strains could achieve similar morphological characteristics with the natural fermentation. Consistently, Jianqu extract from directed fermentation demonstrated a similar therapeutic effect on immune response as that of naturally fermented Jianqu. Conclusions We firstly showed the significant change of structural profiles of fungal communities during Jianqu fermentation, and successfully isolated six dominate fungi strains in Jianqu. Interestingly, directed fermentation for Jianqu with these isolated strains could achieve a similar morphological characteristics and immune-modulating function as natural fermentation. It was suggested that Jianqu fermentation with functional fungi instead of natural microbes provide a new approach for the improvement of the production and quality control of the traditional Chinese medicine of Jianqu.

Bakuchiol (BAK) has been reported to have a diverse pharmacological property as an antibiotic, anti-cancer, anti-hypolipidemic, anti-inflammatory and anti-convulsant agent. This study aimed to elucidate the immunomodulation and anti-inflammatory mechanism of bakuchiol using lipopolysaccharide stimulated RAW 264.7 macrophages and various animal models. The present study has shown that BAK significantly suppressed the pro-inflammatory cytokine expression in a dose-dependent manner and its oral administration significantly decreased delayed hypersensitivity responses as compared to control group. The assessment of immunomodulatory activity was carried out by the testing Hemagglutinating antibody (HA) titer, delayed type hypersensitivity (DTH) responses and phagocytic index by carbon clearance test. On the other hand, it showed significant decrease in circulating antibody titer and carbon clearance assay in a concentration-dependent manner. BAK has significantly potentiated the cellular immunity as well as humoral immunity by facilitating the footpad thickness responses in sheep RBCs in sensitized mice by significantly decreasing circulating antibody titer. Molecular studies revealed that BAK inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. The responses were statistically significant as compared with the control (*p < 0.05, **p < 0.01).

​We retrospectively reviewed the records of 3 patients (3 knees) with a delayed type hypersensitivity reaction following Dermabond exposure after an orthopaedic knee procedure. Delayed hypersensitivity reactions are mediated by CD4+ helper T cells. The use of skin adhesives in place of traditional sutures is increasing in popularity given Dermabond's potential benefits of decreased wound infection rate and better wound approximation. However, hypersensitivity reactions to the cyanoacrylate material in Dermabond have been described. Differentiating hypersensitivity reactions from post-operative infections is important as septic arthritis is a potentially devastating complication. This case series presents the challenge of properly diagnosing and managing hypersensitivity reactions. Consultation with allergists and dermatologists may be appropriate for ascertaining the nature of the surgical site complication and proper management. The recommended management of hypersensitivity-type reactions is a course of topical steroids and infection work up if needed.

Context: The seeds of Buchholzia coriacea Engler (Capparaceae) are used in Eastern Nigeria to treat feverish conditions, and to treat malaria and sleeping sickness that cause fever. Objective: The current study assesses the immunomodulatory activity of Buchholzia coriacea seed extract on Trypanosoma brucei brucei infected mice. Materials and methods: Delayed hypersensitivity reaction, humoral antibody response and in-vivo leucocyte mobilization tests were assessed in three different experiments to determine the effect of the extract on immune response. Seventy-five (75) mice (25 mice per experiment) were used for the study and were each infected with 1.00 × 106 trypanosomes intra-peritoneally. Groups A, B and C were given 250, 500 and 1000 mg/kg of the extract, respectively, group D received 7.5 mg/kg body weight of levamisole and group E was the control. Sheep RBCs were used as antigen. Results: The acute toxicity tests did not cause clinical signs or death within 24 h post treatment at all the doses tested. The extract inhibited delayed hypersensitivity reaction by 20.9 and 20.8% at 250 and 500 mg/kg, respectively, while at 1000 mg/kg, the paw size increased (−101.9%) when compared with the control. The extract elevated the antibody titre from 1.60 ± 0.40 for control to 8.00 ± 3.58 for 500 mg/kg group. The extract increased in total leucocytes counts. Discussion and conclusion: The extract has a very wide safety margin and was able to improve immune response. The results of the present study showed that Buchholzia coriacea seed methanol extract possesses immunostimulatory activity on trypanosome-infected mice.

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.

Eosinophilic esophagitis (EoE) is a chronic inflammatory esophageal disease triggered predominantly, but not excusively, by food antigens. Elimination diet thus remains the only therapy targeting the cause of the disease. Importantly, EoE is a unique form of non-IgE mediated food allergy, largely dependant upon delayed, cell-mediated hypersensitivity. Areas covered: A comprehensive review of literature to summarize and update the most relevant advances on dietary therapy for pediatric and adult EoE patients is conducted. Expert commentary: None of the currently available food allergy tests adequately predict food triggers for EoE, especially in adults. Elemental diet (exclusive feeding with aminoacid-based formulas) and empiric six-food elimination diet, withdrawing cow´s milk, wheat, egg, soy, nuts and fish/seafood for 6 weeks, have consistently shown the best cure rates. However, their high level of restriction and need for multiple endoscopies (top-down approach) have been a deterrent for patients and physicians. Less restrictive empiric schemes, like a four-food (animal milk, gluten-containing cereals, egg, legumes) or a two-food (animal milk and gluten-containing cereals) elimination diet have lately shown encouraging results. Therefore, a novel step-up strategy (2-4-6) may enhance patient uptake and promptly identify most responders to empiric diets with few food triggers, besides saving unnecessary dietary restrictions and endoscopic procedures.

Increasing evidence indicates anti-allergic and anti-inflammatory effects of electro-acupuncture (EA) therapy. However, its underlying mechanism on delayed-type hypersensitivity (DTH), a classic allergic inflammatory disease, still remains unclear. In this study, we aimed to explore the immunomodulatory mechanism of EA intervention in a mouse model of ovalbumin (OVA)-induced DTH. Mice were randomly divided into four groups: Control, OVA-DTH, DTH + EA, DTH + Sham. “Zusanli” acupoint (ST36) was used for DTH + EA, whereas a non-acupoint (localized 5 mm below the “Zusanli” acupoint) was selected for DTH + Sham. Footpad thickness was checked, and the infiltration of inflammatory cells was estimated by hematoxylin and eosin staining. Levels of IgG and IgE in serum of different groups and inflammatory cytokines in the supernatants from homogenized footpads, including IFN-γ, TNF-α, IL-4, and IL-5, were determined by ELISA. Cell proliferation of spleen lymphocytes was assayed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT). The frequency of CD4+IFN-γ+ and CD4+IL-4+ T cells was analyzed with flow cytometry. In addition, the mRNA and protein expression of T-bet and GATA-3 were evaluated by real-time PCR and Western blotting, respectively. Our data showed EA treatment at acupoint ST36 relieved the pathological progression of DTH responses via reduction in footpad swelling, infiltration of inflammatory cells, levels of IgG and IgE as well as decreased production of IFN-γ and TNF-α in homogenized footpad tissue. Moreover, detailed studies were performed revealing that EA attenuated the percentage of CD4+IFN-γ+ T cells and prevented Th cells differentiation into Th1 cells, and this results from inhibiting secretion of IFN-γ and suppressing expression of T-bet, an IFN-γ transcription factor. The results indicated that EA treatment improved Th1-mediated allergic skin inflammation via restoring Th1/Th2 balance by curbing Th1 differentiation. These findings suggested that EA at acupoint ST36 might be a useful and promising therapeutic for allergic inflammatory as well as Th1-mediated inflammation response.

Background Leprosy reactions are immunologically mediated conditions and a major cause of disability before, during and after multidrug therapy. Little data has been published on the epidemiology of leprosy reactions in Bangladesh. Objectives To describe the pattern and prevalence of leprosy reactions in the post elimination stage. Methods A descriptive retrospective cross-sectional study was carried out in Chittagong Medical College Hospital using the registered records of patients the periods between 2004 and 2013. Results Of the 670 leprosy patients 488 (73.38%) were males and 182 (27.37%) were females. The prevalence of reaction was 300 (44.78%) with a male: female ratio of 3.55:1. The age specific cumulative reactions cases at >40 years was high 115 (38.33%) among all age groups. The prevalence of reaction was found to be 166 (55.33%) for the reversal reaction, 49 (16.57%) for the erythema nodosum leprosum and 85 (28.33%) for the neuritis. Borderline tuberculoid was the most common 106 (35.33%) group in reversal reaction while lepromatous leprosy was the most common 37 (12.33%) in erythema nodosum leprosum. More than half of the patients 169 (56.33%) had reactions at the time of presentations while 85 (28.33%) and 46 (15.33%) of patients developed reaction during and after multidrug therapy respectively. The reversal reaction group presented with ≥ 6 skin lesions in 96 (57.83%) and ≥ 2 nerves involvement in 107 (64.46%) patients. The erythema nodosum leprosum presented chiefly as papulo-nodular 45 (91.84%) lesions followed by pustule-necrotic 4 (8.16%) lesions, neuritis 33 (67.35%), fever 24 (48.98%), lymphadenitis 6 (12.24%), arthritis 5 (10.20%) and iritis 2 (4.08%). Bacterial index ≥ 3 had been demonstrated in 34 (60.71%) patients of erythema nodosum leprosum. Conclusion The incidence of leprosy reaction seemed to be more than three times common in borederline tuberculoid (52.33%) than in lepromatous leprosy (14%). Reactions with nerve function impairment and disability still occur among multibacillary patients during and after multidrug therapy. Early detection and management of leprosy reaction is very important in preventing disability and deformity, and patients should be educated to undergo regular follow-up examinations. Developing reinforced new therapies to curb leprosy reactions is crucial for improving leprosy health care services. This article is protected by copyright. All rights reserved.

Purpose of review: Antimicrobials are a leading cause of severe T cell-mediated adverse drug reactions (ADRs). The purpose of this review is to address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for in-vitro, in-vivo, and ex-vivo diagnostics for T cell-mediated ADRs. Recent findings: Recent literature has evaluated the efficacy of traditional antibiotic allergy management, including patch testing, skin prick testing, intradermal testing, and oral challenge. Although patch and intradermal testing are specific for the diagnosis of immune-mediated ADRs, they suffer from drug-specific limitations in sensitivity. The use of ex-vivo diagnostics, especially enzyme-linked immunospot, has been highlighted as a promising new approach to assigning causality. Knowledge of true rates of antimicrobial cross-reactivity aids empirical antibiotic choice in the setting of previous immune-mediated ADRs. Summary: In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct ‘allergy label’ is essential. Re-exposure to implicated antimicrobials, especially in the setting of severe adverse cutaneous reaction, is associated with significant morbidity and mortality. The process through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines.

In this MiniReview, we summarize the body of knowledge on the delayed-type hypersensitivity arthritis (DTHA) model, a recently developed arthritis model with 100% incidence, low variation and synchronized onset in C57BL/6 (B6) mice, and compare it to other murine arthritis models. It is desirable to have robust arthritis models in B6 mice, as many transgene strains are bred on this background. However, several of the most widely used mouse model of arthritis cannot be induced in B6 mice without the drawback of lower incidence, reduced severity and higher variation, if at all. DTHA is induced by modifying a classical methylated bovine serum albumin (mBSA)-induced DTH response by administering a cocktail of anti-type II collagen antibodies (anti-CII) between immunization and challenge. Arthritis affects one, predefined paw in which acute inflammation and severe arthritis rapidly develop and peak after 4-7 days. Disease is self-resolving over the course of around 3 weeks. Disease manifestations resemble those seen in other arthritis models and include bone erosion, cartilage destruction, oedema, pannus and new bone formation. Induction of DTHA is dependent on CD4+ T cells while B cells are dispensable. The DTHA model is set apart from other murine arthritis models in that it can be induced in B6 mice with 100% incidence and with high and consistent severity. This is the clearest advantage of the model, as the mechanisms of disease and clinical manifestations can be found in other arthritis models. The model holds potential for future modifications that may improve the lack of chronicity.