Delayed-type Hypersensitivity Response Research Articles

Immune Regulation by TNF Receptor-associated Factor 5

The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of molecules are intracellular adaptors that regulate cellular signaling through members of the TNFR and Toll-like receptor superfamily. Mammals have seven TRAF molecules numbered sequentially from TRAF1 to TRAF7. Although TRAF5 was identified as a potential regulator of TNFR superfamily members, the in vivo function of TRAF5 has not yet been fully elucidated. We identified an unconventional role of TRAF5 in interleukin-6 (IL-6) receptor signaling involving CD4+ T cells. Moreover, TRAF5 binds to the signal-transducing glycoprotein 130 (gp130) receptor for IL-6 and inhibits the activity of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. In addition, Traf5-deficient CD4+ T cells exhibit significantly enhanced IL-6-driven differentiation of T helper 17 (Th17) cells, which exacerbates neuroinflammation in experimental autoimmune encephalomyelitis. Furthermore, TRAF5 demonstrates a similar activity to gp130 for IL-27, another cytokine of the IL-6 family. Additionally, Traf5-deficient CD4+ T cells display significantly increased IL-27-mediated differentiation of Th1 cells, which increases footpad swelling in delayed-type hypersensitivity response. Thus, TRAF5 functions as a negative regulator of gp130 in CD4+ T cells. This review aimed to explain how TRAF5 controls the differentiation of CD4+ T cells and discuss how the expression of TRAF5 in T cells and other cell types can influence the development and progression of autoimmune and inflammatory diseases.

Antimicrobial and Antiplasmodial Activities of Endophytic Fungi Associated with Psidium guajava

Infections due to antimicrobial-resistant microorganisms have become widespread in recent years. Thus, searching for novel antimicrobial agents to combat such pathogens has become crucial. The current study aimed to evaluate the antimicrobial, antiplasmodial, and immunomodulatory activities of the extracts of endophytic fungi isolated from Psidium guajava. Isolation, identification, fermentation, and extraction of the secondary metabolites of the fungal endophytes were carried out following standard procedures. The extracts were subjected to High-Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD) analysis to detect their bioactive components. The Antimicrobial activity and Minimum Inhibitory Concentration of the fungal extracts were evaluated against pure cultures of Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumonia using Agar well diffusion and Agar dilution method respectively. The acute toxicity study (LD50) was carried out using Lorke’s method. The extracts were tested in vivo in mice for antiplasmodial activity against Plasmodium berghei and in vitro against Plasmodium falciparum using Peter and Reyley's curative test method and WHO standardized micro-test system with modification respectively. The immunomodulatory activity of the extracts was evaluated by cyclophosphamide-induced myelosuppression (hematological parameters). Active extracts were further subjected to Delayed-Type Hypersensitivity Response (DTHR) and Haemagglutination Inhibition Assay using Sheep Red Blood Cells as antigens. The result showed Alternaria sp. (PGL1, PGL2, PGL3), from P. guajava. The HPLC-DAD analysis revealed the presence of bioactive compounds previously reported to have antimicrobial, antiplasmodial, and immunomodulatory properties. The fungal extracts exhibited varying degrees of antimicrobial activity. The LD50 of the fungi extracts was>5000 mg/kg in mice. The extracts at 100 and 200 mg/kg body weight in mice showed varying degrees of antiplasmodial activity. Growth of P. berghei was significantly (p<0.001) inhibited, curative effect ranges from 59.09 – 100%. Schizont maturation of P. falciparum isolates was inhibited and the highest level of inhibition was observed at 1 mg/ml (p<0.05). The fungal extracts reversed the effect of cyclophosphamide-induced reduction in total white blood cell counts and % neutrophil. This study showed that the tested plant harbors species of endophytic fungi that contain numerous secondary metabolites. The endophytic fungi showed prophylactic, immunostimulatory, and antiplasmodial activities, which can be exploited to develop antimicrobial, antiplasmodial, and immunomodulatory agents.

Chicory root powder included as a prebiotic in different cereal-based diets for dogs: Influences on gut health, metabolic and immunological status

The present experiment was conducted to study the influence of chicory root powder as a prebiotic on gut health, metabolic, and immunological status of dogs fed with different cereal-based diets. Sixteen Labrador dogs, fed either a wheat (WT) or sorghum (SG) based diet, each without (C) or with (P) supplemental chicory root powder at 10 g/kg diet, were divided into four equal groups namely WT-C, WT-P, SG-C and SG-P. The digestibility of DM, OM, and total carbohydrates was significantly (p < 0.05) higher with the SG-C diet than with the other diets. Faecal ammonia was reduced (p = 0.002) in the WT-P group; however, there were no differences (p > 0.05) observed in the faecal pH and contents of lactate, acetate, propionate and total short chain fatty acids (SCFAs). The faecal lactobacilli population was higher (p = 0.001) in both the prebiotic-supplemented groups with a similar trend (p = 0.079) for bifidobacteria. Coliform counts were reduced (p = 0.002) in prebiotic-supplemented diets irrespective of cereals. There were significant (p < 0.05) variations in haemoglobin and haematocrit values among the dietary groups. The delayed-type hypersensitivity response to intradermal phytohemagglutinin (PHA-P) was higher (p<0.001) in both the prebiotic-supplemented groups; a similar trend was evident in the humoral immune response measured as antibody response to sheep erythrocytes. The peripheral lymphocyte subpopulations of CD4+ and CD8+ varied with prebiotic supplementation of the sorghum-based diet. Overall, the findings implies that tailoring the dietary composition to include specific cereals may optimize the beneficial effects of prebiotics in supporting canine health.

Immunomodulation Induced in BALB/c Mice after Subacute Exposure to Hydroalcoholic Extract of Artimisia Dracunculus.

Tarragon, with the scientific name of Artemisia dracunculus, is a perennial herbaceous plant with a wide spectrum of pharmacologic properties. In the current investigation, BALB/c mice were used to examine the immunomodulatory effects of hydroalcoholic extract of tarragon (HET). Mice were treated with hydroalcoholic extract of Artimisia dracunculus (HET) at two doses (250 and 500 mg/kg) for 14 days. The host hematological parameters, spleen cellularity histopathology, hemagglutination titer assay (HA), delayed-type hypersensitivity (DTH) responses, IFN-γ and IL-4 levels produced by spelenocytes, and the proliferation of lymphocytes were assayed. HET at a high dose significantly could increase the number of white blood cells and lymphocytes compared to the control group. The lymphocyte proliferation in exposure to PHA significantly increased in the HET group at both doses compared to the control group, whilst this index in the presence of LPS increased significantly for the 500 mg/kg-HET group only. Moreover, in the HA and DTH tests, HET significantly increased the proliferation of lymphocytes as compared with the control group. Furthermore, HET significantly increased the amount of IFN-γ parallel to a decrease in the level of IL-4 in compared to the control group. Based on our findings, HET has potent immunostimulant characteristics. More investigation into tarragon's potential to be used in the treatment of disorders caused by a weakened immune response should be conducted.

Immunomodulatory effects of epiphytic Loranthus micranthus leaf extracts collected from two host plants: Psidium guajava and Parkia biglobosa

BackgroundImmunological abnormalities are implicated in the pathogenesis of many chronic diseases. Due to the drug-related adverse effects of currently available orthodox immunomodulators, natural immunomodulators are being looked upon as potential agents to replace them in therapeutic regimens. This research aimed to investigate the immunomodulatory potential of L. micranthus extracts epiphytic on Psidium guajava (LMPGE) and Parkia biglobosa (LMPBE).MethodsPhytochemical screening and acute toxicity testing were carried out to identify the phytoconstituents and safety profiles of the extracts. The extracts’ innate and adaptive immunomodulatory potentials were determined in experimental animals using in vivo leucocyte mobilization, delayed-type hypersensitivity (DTH) response, hemagglutination antibody titre, and cyclophosphamide-induced myelosuppression models. Levamisole was used as the standard drug throughout the study.ResultsCompared to LMPBE, LMPGE contained significantly (p < 0.05) more tannins, cyanogenic glycosides, saponins, reducing sugars, glycosides, flavonoids, and alkaloids. Furthermore, the groups treated with the extracts had a significant (p < 0.05) increase in the total number of leucocytes, neutrophils, basophils, and antibody titers relative to the untreated control. In the same way, the treatment raised TLC in cyclophosphamide-intoxicated rats, with 250 mg/kg b. w. of LMPGE and LMPBE recording 9712.50 ± 178.00 and 8000.00 ± 105.00 × 109 /L, respectively, compared to 3425.00 ± 2 5.00 × 109 /L in the untreated group. Overall, LMPGE was more effective.ConclusionsThe findings from this study suggest that L. micranthus epiphytic in Psidium guajava and Parkia biglobosa has possible immune stimulating potential.

In Vitro and In Vivo Methods for Analysis of Nanoparticles' Potential toInduce Delayed-Type Hypersensitivity Reactions.

Delayed-type hypersensitivity (DTH) reactions are among the common reasons for drug withdrawal from clinical use during the post-marketing stage. Several in vivo methods have been developed to test DTH responses in animal models. They include the local lymph node assay (LLNA) and local lymph node proliferation assay (LLNP). While LLNA is instrumental in testing topically administered formulations (e.g., creams), the LLNP was proven to be predictive of drug-mediated DTH in response to small molecule pharmaceuticals. Global efforts in reducing the use of research animals lead to the development of in vitro models to predict test-materials' mediated DTH. Two such models include theanalysis of surface marker expression in human cell lines THP-1 and U-937. These tests are known as the human cell line activation test (hCLAT) and myeloid U937 skin sensitization test (MUSST or U-SENS), respectively. Here we describe experimental procedures for all these methods, discuss their in vitro-in vivo correlation, and suggest a strategy for applying these tests to analyze engineered nanomaterials and nanotechnology-formulated drug products.

Investigation of immunomodulatory activity of hericium erinaceus on cyclophosphamide-induced immunosuppression in mice

The study was conducted to assess the immunostimulatory effect of Hericium Erinaceus on cyclophosphamide-induced immunodeficient mice. Animals were administered Hericium Erinaceus orally at 0.72 g/kg b.w and 1.44 g/kg b.w for seven consecutive days. On the 4th day, CP (200 mg/kg) was intraperitoneally injected into mice. The results illustrated that Hericium Erinaceus at 0.72 g/kg b.w only posed an immunostimulating potency in the cyclophosphamide-induced immunosuppression model. Besides, Hericium Erinaceus at 1.44 g/kg b.w ameliorated the effects of CP on delayed-type hypersensitivity (DTH) response, relative spleen weight, serum IL-2, TNF-α concentration, and micro-histological images of spleen and thymus substantially. This suggested the potential of Hericium Erinaceus to treat immunosuppression diseases in clinical practice.

The role of intralesional immunotherapy in Condyloma Acuminata

Intralesional immunotherapy is one of the immunotherapy modalities that can be given to patients with condyloma acuminata (CA) with a high success rate both in inhibiting progression and preventing recurrence of genital warts. Intralesional immunotherapy regimens that are currently being studied are the use of vaccines and cytokines. Some of the antigens studied for use as therapy in genital warts include Candida albicans, measles, mumps and rubella (MMR), and Tuberculin/Purified Protein Derivate (PPD), Mycobacterium w, and Bacille Calmette-Guerin (BCG). Vaccines and cytokines work by inducing a delayed-type hypersensitivity response to warts tissue, both through cellular and humoral immune responses, mediated by CD8+ T lymphocytes, CD4+ T lymphocytes, B lymphocytes and regulatory T cells so that this can eliminate HPV virus infection in CA. This literature review aims to provide an understanding of the use of intralesional immunotherapy as an effective alternative therapy in CA.

IMMUNOSTIMULANT ACTIVITY OF HANTAP (STERCULIA COCCINEA JACK) LEAVES EXTRACT ON NON-SPECIFIC AND SPESIFIC IMMUNE RESPONSES

Objective: This study aims to determine the immunostimulant effect and the effective dose of hantap leaf ethanolic extract against non-specific and specific immune responses.&#x0D; Methods: The immunostimulant activity of the extract was tested by the carbon clearance method (non-specific response). The effect of the extract on delay-type hypersensitivity/DTH (cellular-specific response) was determined by the paw edema method. The number of leukocyte cells and the percentage of leukocyte cell types were also calculated. The antibody titer (humoral-specific response) test was carried out by the hemagglutination method.&#x0D; Results: The results of the non-specific immune response demonstrated that three doses of hantap leaf extract, when compared to the negative control, could accelerate the rate of carbon elimination and increase the phagocytosis index. Hantap leaf extract can provide an immunomodulatory effect by increasing the delayed-type hypersensitivity response by showing a greater volume of leg swelling than the negative control received CMC Na 0.5%, which was significantly different (p&lt;0.05), increasing leukocyte count and leukocyte differential and increasing primary and secondary antibody titers. The effective dose of hantap leaves extract was 200 mg/kg body weight.&#x0D; Conclusion: This study proves that hantap leaf extract has an immunomodulatory effect that increases the immune system (immunostimulant)

A Comparative Study on the Mechanism of Delayed-Type Hypersensitivity Mediated by the Recombinant Mycobacterium tuberculosis Fusion Protein ESAT6-CFP10 and Purified Protein Derivative

While purified protein derivative (PPD) is commonly used as skin diagnostic reagent for tuberculosis (TB) infection, it cannot distinguish effectively Bacillus Calmette–Guérin (BCG) vaccination from Mycobacterium tuberculosis (MTB) complex and nontuberculous mycobacteria infection. The new skin reagent ESAT6-CFP10 (EC) has favorable sensitivity and specificity, which can overcome limitations associated with PPD. At present, EC skin test reactions are mainly characterized by erythema, while PPD mainly causes induration. We conducted a comparative study on the potential differences between EC-induced erythema and PPD-induced induration using a guinea pig model. The size of EC-dependent erythema was similar to that of PPD-induced induration, and an inflammatory response characterized by the infiltration of monocytes, macrophages and lymphocytes, as well as tissue damage, appeared at the injection site. The lymphocytes included CD4+ T and CD8+ T cells, which released IFN-γ as the main cytokine. Both EC erythema and PPD induration could lead to increased levels of acute-phase proteins, and the differential pathways were similar, thus indicating that the main induced immune pathways were similar. The above results indicated that erythema produced by EC could generate the main delayed-type hypersensitivity (DTH) response characteristic of PPD induration, thereby suggesting that erythema might also have a certain diagnostic significance and provide a possible theoretical basis for its use as a diagnostic indicator for detecting MTB infection.

Headache as initial presentation of human chronic necrotizing granulomatous meningoencephalitis: A rare case report

Chronic necrotizing granulomatous meningoencephalitis is an idiopathic inflammatory disease with possible autoimmune mediated delayed type hypersensitivity response. It commonly affects the central nervous system of dogs, and on rare occasions cats. However, this inflammatory disease has rarely been reported in humans. A 69-year-old woman presented with subacute intermittent sharp headaches. Brain MRI revealed multifocal enhancing lesions and edema as well as multifocal signal abnormality throughout the supratentorial and infratentorial parenchyma. Cerebrospinal fluid showed elevated opening pressure, pleocytosis, and elevated protein. MRA head, MRV head, cerebral angiogram, extensive serum and CSF work up for infectious and autoimmune etiologies were also unremarkable. Brain biopsy revealed necrotizing granulomatous inflammation with dystrophic calcification. High dose of methylprednisolone followed by a 6-week prednisone taper resolved her headache and the brain MRI abnormalities. This case demonstrates the response of necrotizing granulomatous meningoencephalitis in humans to steroids.

Isolation of a novel pentasaccharide Ebaliose from immunostimulant fraction of buffalo milk oligosaccharide

Buffalo milk processed by method of Kobata and Ginsburg for isolation of its oligosaccharide contents showed significant stimulation of anti-body, delayed type hypersensitivity response to sheep red blood cells in BALB/c mice. This oligosaccharide mixture also stimulated non-specific immune response in terms of MMI. In continuation to our previous studies of oligosaccharide contents of buffalo milk another novel pentasaccharide Ebaliose was isolated from immunostimulant oligosaccharide fraction of buffalo milk. Ebaliose was procured in its purest form, by combining the different chromatographic techniques like Gel filtration, Silica Gel column chromatography, and HPLC. The structure of novel oligosaccharide was determined by 1H,13C, HSQC, TOCSY, COSY, HMBC, ESI-MS, chemical transformation, and chemical degradation. The stereoscopic structure of this novel pentasaccharide was established as under.

FORMULATION AND EVALUATION OF HERBAL CAPSULE CONTAINING CURCUMA MANGGA VALETON and ZIJP. EXTRACT AND ITS IMMUNOSTIMULATORY EFFECTS

Objective: The present study was carried out to formulate and evaluate C. mangga extract as granule mass in a capsule dosage form as well as investigate its immunostimulatory effects. Methods: The granule mass was evaluated for its bulk density, tapped density, Carr’s index, Hausner ratio, angle of repose, and flow ability. Meanwhile, capsule weight and disintegration time were determined to evaluate the C. mangga capsule. The immunostimulatory effects of extract in capsule dosage form were investigated by measuring delayed-type hypersensitivity (DTH) response and IgG production. There were six formula prepared (F1-F6). Formula F1-F6 were vary according to the component of adsorbent (Corn starch/polyvinyl pyrrolidone) and filler (maltodextrin/Avicel/lactose) to obtain the optimum formula. Results: The granule mass of all formula had a good flow ability and free-flowing properties according to the Carr’s index (10.26±3.38 to 17.54±1.60) and flowing time (1.05±0.05 to 1.60±0.08 seconds). Of all the capsule formula, F2 capsule containing dry extract of C. mangga with Avicel as the filler met the standard requirement in terms of disintegration time (2.15±0.76 min) and weight uniformity (the deviation was below than 7.5%). The capsule of C. mangga extract enhanced the paw thickness as compared to those of the negative control (P&lt;0.05). The level of Immunoglobulin G (IgG) was also increased after treatment with the capsule of C. mangga extract. Conclusion: The results suggest that the capsule of C. mangga extract has immunostimulatory effects, emphasizing its potential to be used for the treatment of infectious and immunodeficiency diseases.

Melittin as a safe compound to BALB/c mice immune system; a tiered approach immunotoxicity screening

BackgroundMaintenance of immune system integrity is a vital requirement to protect human body against pathogens/cancers. Natural compounds have long been used due to their benefits for the immune system. One of which is bee venom that contains a peptide called melittin having antimicrobial and anticancer effects. Since a limited number of studies regarding the effects of melittin on the immune system have been carried out, we aimed to evaluate the effects of melittin on BALB/c mice immune system parameters.MethodsFemale BALB /c mice were treated intraperitoneally (i.p) with 0.75 and 1.5 mg/kg doses of melittin for 14 days (5 doses per week). The negative control group received i.p normal saline whereas the positive controls received i.p 20 mg/kg cyclophosphamide (CYP). Immunological parameters such as hematological parameters, delayed-type hypersensitivity (DTH), hemagglutination titer (HA), spleen cellularity, splenocytes proliferation, as well as spleen and bone marrow histopathological assessment were evaluated.ResultsOur findings showed that melittin has no gross pathological effect on the spleen and bone marrow. It was also demonstrated that melittin has no any significant effect on hematological parameters. Melittin did not cause any significant changes to proliferation response of splenocytes to PHA and LPS, spleen cellularity, DTH response, as well as the production of anti-SRBC antibodies. According to our results, melittin at 0.75 and 1.5 mg/kg doses could not induce significant changes on immune parameters and as a result, melittin was found to be safe for the mice immune system.

Comparison of the effects of probiotic strains (Lactobacillus gasseri, Lactiplantibacillus plantarum, Lactobacillus acidophilus, and Limosilactobacillus fermentum) isolated from human and food products on the immune response of CT26 tumor-bearing mice.

This study aimed to compare the effects of the probiotic bacteria, L. gasseri (52b), L. plantarum (M11), L. acidophilus (AC2), and L. fermentum (19SH), isolated from human source and traditional food products on the modulation of the immune system and inflammatory response on BALB/c mouse model bearing CT26 tumor. Five groups of female inbred BALB/c mice were orally administered with the probiotics and their mixes (MIX, at a 1:1 ratio) at varying dosages (1.5 × 108cfu/ml and 1.2 × 109cfu/ml) before and after the injection of a subcutaneous CT26 tumor over the course of 38days via gavage. Finally, their effects on the tumor apoptosis and the cytokine levels in spleen cell cultures were analyzed and compared. M11, MIX, and 52b groups had the greatest levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) production. The highest production level of granzyme B (GrB) was related to the MIX and 52b groups. Moreover, these groups showed the lowest production level of (IL-4) and transforming growth factor beta (TGF-β). Furthermore, the groups of MIX and 52b demonstrated the greatest amount of lymphocyte proliferation of spleen cells in response to the tumor antigen. The delayed-type hypersensitivity (DTH) response significantly increased in the groups of MIX and 52b compared with the control (p < 0.05). The findings demonstrated that the oral treatment of the human strain (52b) and the combination of these bacteria generated strong T helper type 1 (Th1) immune responses in the tumor tissue of the tumor-bearing mice, which led to the suppression of the tumor development.

Individual and sociodemographic factors associated with polysensitization at a New York City hospital

Allergic contact dermatitis (ACD) is a cutaneous delayed-type hypersensitivity response with a global prevalence estimated at over 20%.1 The gold standard for diagnosis is patch testing, in which allergens are applied to a patient's skin to elicit cutaneous responses in sensitized individuals. Many patients undergoing patch testing test positive for 3 or more unrelated allergens, termed polysensitization.2 A recent North American Contact Dermatitis Group study found that 32.1% of patients tested were positive to at least three allergens, but reported rates vary.3

Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes.

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc-scOX40L, Fc-sc4-1BBL, Fc-scCD27L (CD70) and Fc-scGITRL. Without intentional cross-linking, these soluble Fc-scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc-scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc-scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins.

Nasal immunization with H7 flagellin protects mice against hemolytic uremic syndrome secondary to Escherichia coli O157:H7 gastrointestinal infection.

Shiga-toxin (Stx) producing Escherichia coli (STEC) O157:H7 is the most frequent serotype associated with hemolytic uremic syndrome (HUS) after gastrointestinal infections. Protection against HUS secondary to STEC infections has been experimentally assayed through the generation of different vaccine formulations. With focus on patients, the strategies have been mainly oriented to inhibit production of Stx or its neutralization. However, few approaches have been intended to block gastrointestinal phase of this disease, which is considered the first step in the pathogenic cascade of HUS. The aim of this work was to assay H7 flagellin as a mucosal vaccine candidate to prevent the systemic complications secondary to E. coli O157:H7 infections. The cellular and humoral immune response after H7 nasal immunization in mice were studied by the analysis of systemic and intestinal specific antibody production, as well as cytokine production and lymphocyte proliferation against H7 flagellin ex vivo. Immunized mice developed a strong and specific anti-H7 IgG and IgA response, at systemic and mucosal level, as well as a cellular Th1/Th2/Th17 response. H7 induced activation of bone marrow derived dendritic cells in vitro and a significant delayed-type hypersensitivity (DTH) response in immunized mice. Most relevant, immunized mice were completely protected against the challenge with an E. coli O157:H7 virulent strain in vivo, and surviving mice presented high titres of anti-H7 and Stx antibodies. These results suggest that immunization avoids HUS outcome and allows to elicit a specific immune response against other virulence factors.

Quillaja brasiliensis nanoparticle adjuvant formulation improves the efficacy of an inactivated trivalent influenza vaccine in mice.

The threat of viral influenza infections has sparked research efforts to develop vaccines that can induce broadly protective immunity with safe adjuvants that trigger robust immune responses. Here, we demonstrate that subcutaneous or intranasal delivery of a seasonal trivalent influenza vaccine (TIV) adjuvanted with the Quillaja brasiliensis saponin-based nanoparticle (IMXQB) increases the potency of TIV. The adjuvanted vaccine (TIV-IMXQB) elicited high levels of IgG2a and IgG1 antibodies with virus-neutralizing capacity and improved serum hemagglutination inhibition titers. The cellular immune response induced by TIV-IMXQB suggests the presence of a mixed Th1/Th2 cytokine profile, antibody-secreting cells (ASCs) skewed toward an IgG2a phenotype, a positive delayed-type hypersensitivity (DTH) response, and effector CD4+ and CD8+ T cells. After challenge, viral titers in the lungs were significantly lower in animals receiving TIV-IMXQB than in those inoculated with TIV alone. Most notably, mice vaccinated intranasally with TIV-IMXQB and challenged with a lethal dose of influenza virus were fully protected against weight loss and lung virus replication, with no mortality, whereas, among animals vaccinated with TIV alone, the mortality rate was 75%. These findings demonstrate that TIV-IMXQB improved the immune responses to TIV, and, unlike the commercial vaccine, conferred full protection against influenza challenge.

Mesenchymal Stromal Cells Suppress T-Cell-Mediated Delayed-Type Hypersensitivity via ALCAM-CD6 Interaction.

Mounting evidence suggests mesenchymal stromal cells (MSCs) suppress CD4+ T-cell activation, but whether MSCs directly regulate activation and expansion of allogeneic T cells has not been fully deciphered. Here, we identified that both human and murine MSCs constitutively express ALCAM, a cognate ligand for CD6 receptors on T cells, and investigated its immunomodulatory function using in vivo and in vitro experiments. Our controlled coculture assays demonstrated that ALCAM-CD6 pathway is critical for MSCs to exert its suppressive function on early CD4+CD25- T-cell activation. Moreover, neutralizing ALCAM or CD6 results in the abrogation of MSC-mediated suppression of T-cell expansion. Using a murine model of delayed-type hypersensitivity response to alloantigen, we show that ALCAM-silenced MSCs lose the capacity to suppress the generation of alloreactive IFNγ-secreting T cells. Consequently, MSCs, following ALCAM knockdown, failed to prevent allosensitization and alloreactive T-cell-mediated tissue damage.