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1. Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model

Author

Carlos D. Zappia, Ariadna Soto, Gina Granja‐Galeano, Ignacio Fenoy, Natalia Fernandez, Carlos A. Davio, Carina Shayo, Carlos P. Fitzsimons, Alejandra Goldman, and Federico Monczor

Subjects
antihistamines, asthma, azelastine, dexamethasone, glucocorticoids, histamine, Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Glucocorticoids are among the most effective drugs to treat asthma. However, the severe adverse effects associated generate the need for its therapeutic optimization. Conversely, though histamine is undoubtedly related to asthma development, there is a lack of efficacy of antihistamines in controlling its symptoms, which prevents their clinical application. We have reported that antihistamines potentiate glucocorticoids’ responses in vitro and recent observations have indicated that the coadministration of an antihistamine and a synthetic glucocorticoid has synergistic effects on a murine model of allergic rhinitis. Here, the aim of this work is to establish if this therapeutic combination could be beneficial in a murine model of asthma. We used an allergen‐induced model of asthma (employing ovalbumin) to evaluate the effects of the synthetic glucocorticoid dexamethasone combined with the antihistamine azelastine. Our results indicate that the cotreatment with azelastine and a suboptimal dose of dexamethasone can improve allergic lung inflammation as shown by a decrease in eosinophils in bronchoalveolar lavage, fewer peribronchial and perivascular infiltrates, and mucin‐producing cells. In addition, serum levels of allergen‐specific IgE and IgG1 were also reduced, as well as the expression of lung inflammatory‐related genes IL‐4, IL‐5, Muc5AC, and Arginase I. The potentiation of dexamethasone effects by azelastine could allow to reduce the effective glucocorticoid dose needed to achieve a therapeutic effect. These findings provide first new insights into the potential benefits of glucocorticoids and antihistamines combination for the treatment of asthma and grants further research to evaluate this approach in other related inflammatory conditions.

Published
2019
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2. Toxoplasma gondii serine-protease inhibitor-1: A new adjuvant candidate for asthma therapy.

Author

Ariadna S Soto, Ignacio M Fenoy, Vanesa R Sanchez, Florencia March, Matías D Perrone Sibilia, María de Los Angeles Aldirico, Mariano S Picchio, Nadia Arcon, Patricio L Acosta, Fernando P Polack, Valentina Martin, and Alejandra Goldman

Subjects
Medicine, Science
Abstract

Serine-proteases are important players in the pathogenesis of asthma, promoting inflammation and tissue remodeling. It's also known that many serine protease inhibitors display immunomodulatory properties. TgPI-1 is a Toxoplasma gondii protein that exhibits broad spectrum inhibitory activity against serine proteases. In view of the increased prevalence of atopic disorders and the need to develop new treatment strategies we sought to investigate the potential of TgPI-1 for treating respiratory allergies. For this purpose, we developed a therapeutic experimental model. BALB/c mice were rendered allergic by intraperitoneal ovalbumin-alum sensitization and airway-challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with rTgPI-1 alone or with a mixture of rTgPI-1 and ovalbumin (OVA). A week later mice were given a secondary aerosol challenge. Treatment with rTgPI-1 alone or co-administered with OVA diminished bronchoalveolar eosinophilia, mucus production and peribronchial lung infiltration. This effect was accompanied by a lung resistance reduction of 26.3% and 50.3% respectively. Both treatments resulted in the production of lower levels of IL-4, IL-5, IFN-γ and regulatory IL-10 by thoracic lymph node cells stimulated with OVA. Interestingly, significant decreases in OVA specific IgE and T cell proliferation, and increases in FoxP3+ T cells at local and systemic levels were only detected when the inhibitor was administered along with OVA. These results show that both rTgPI-1 treatments reduced asthma hallmarks. However, co-administration of the inhibitor with the allergen was more effective. Hence, rTgPI-1 emerges as a novel adjuvant candidate for asthma treatment.

Published
2017
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3. Toxoplasma gondii infection induces suppression in a mouse model of allergic airway inflammation.

Author

Ignacio M Fenoy, Romina Chiurazzi, Vanesa R Sánchez, Mariana A Argenziano, Ariadna Soto, Mariano S Picchio, Valentina Martin, and Alejandra Goldman

Subjects
Medicine, Science
Abstract

Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact-independent and correlated with high levels of TGF-β and CD4(+)FoxP3(+) cells.

Published
2012
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4. Plant Hsp90 proteins interact with B-cells and stimulate their proliferation.

Author

Mariana G Corigliano, Andrea Maglioco, Melina Laguía Becher, Alejandra Goldman, Valentina Martín, Sergio O Angel, and Marina Clemente

Subjects
Medicine, Science
Abstract

BACKGROUND: The molecular chaperone heat shock protein 90 (Hsp90) plays an important role in folding stabilization and activation of client proteins. Besides, Hsp90 of mammals and mammalian pathogens displays immunostimulatory properties. Here, we investigated the role of plant-derived Hsp90s as B-cell mitogens by measuring their proliferative responses in vitro. METHODOLOGY: Plant cytosolic Hsp90 isoforms from Arabidopsis thaliana (AtHsp81.2) and Nicotiana benthamiana (NbHsp90.3) were expressed in E. coli. Over-expression of recombinant plant Hsp90s (rpHsp90s) was confirmed by SDS-PAGE and western blot using and anti-AtHsp81.2 polyclonal anti-body. Both recombinant proteins were purified by Ni-NTA affinity chromatography and their identity confirmed by MALDI-TOF-TOF. Recombinant AtHsp81.2 and NbHsp90.3 proteins induced prominent proliferative responses in spleen cells form BALB/c mice. Polymyxin-B, a potent inhibitor of lipopolysaccharide (LPS), did not eliminate the rpHsp90-induced proliferation. In addition, in vitro incubation of spleen cells with rpHsp90 led to the expansion of CD19-bearing populations, suggesting a direct effect of these proteins on B lymphocytes. This effect was confirmed by immunofluorescence analysis, where a direct binding of rpHsp90 to B- but not to T-cells was observed in cells from BALB/c and C3H/HeN mice. Finally, we examined the involvement of Toll Like Receptor 4 (TLR4) molecules in the rpHsp90s induction of B-cell proliferation. Spleen cells from C3H/HeJ mice, which carry a point mutation in the cytoplasmic region of TLR4, responded poorly to prAtHsp90. However, the interaction between rpHsp90 and B-cells from C3H/HeJ mice was not altered, suggesting that the mutation on TLR4 would be affecting the signal cascade but not the rpHsp90-TLR4 receptor interaction. CONCLUSIONS: Our results show for the first time that spleen cell proliferation can be stimulated by a non-pathogen-derived Hsp90. Furthermore, our data provide a new example of a non-pathogen-derived ligand for TLRs.

Published
2011
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5. Contribution of Kazal-Like Domains of the Serine Protease Inhibitor-1 from Toxoplasma gondii in Asthma Therapeutic Vaccination Effectiveness

Author

Ariadna Soto, Matías Perrone Sibilia, Vanesa Roxana Sánchez, Nadia Arcón, Valentina Martin, Ignacio Martín Fenoy, and Alejandra Goldman

Subjects
Immunology, Immunology and Allergy, General Medicine
Abstract

Background: We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. Objectives: In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. Methods: BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. Results: Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. Conclusions: Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.

Published
2022
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6. Synergistic effect of GRA7 and profilin proteins in vaccination against chronic Toxoplasma gondii infection

Author

Valentina Martin, Cecilia A. Prato, Mariano Sergio Picchio, Ariadna Soledad Soto, Ignacio Martín Fenoy, Nadia Arcon, Alejandra Goldman, Rosalia Moretta, María Virginia Tribulatti, Vanesa Roxana Sánchez, and Matías D. Perrone Sibilia

Subjects
Protozoan Vaccines, Cellular immunity, 030231 tropical medicine, Protozoan Proteins, Antibodies, Protozoan, Antigens, Protozoan, Lymphocyte proliferation, Mice, Profilins, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Immunity, Animals, 030212 general & internal medicine, Mice, Inbred BALB C, Innate immune system, General Veterinary, General Immunology and Microbiology, biology, Vaccination, Public Health, Environmental and Occupational Health, Toxoplasma gondii, biology.organism_classification, Toxoplasmosis, Animal, Infectious Diseases, Immunology, Cytokines, Molecular Medicine, Toxoplasma
Abstract

Toxoplasmosis is a zoonotic disease with worldwide prevalence in humans and warm-blooded animal populations. In livestock Toxoplasma gondii is the causal agent of significant economic losses since it can cause abortions in goats and sheep. It is estimated that one third of the world population is infected. Although there are effective therapies for acute infection, these are sometimes poorly tolerated, teratogenic, and have a long administration time. Considering the deficiencies that exist related to the prevention and treatment of toxoplasmosis, the development of a safe and effective vaccine would be extremely valuable in fighting against this infection. In the present work, we characterize for the first time the adjuvant and immunogenic potential of a recombinant profilin protein (rTgPF), in a vaccine formulation alone or in combination with the well-known GRA7 antigen candidate in a murine toxoplasmosis model. Since TgPF acts as a ligand for TLR11 and 12 inducing innate immune responses that promote type 1 adaptive responses, we first study the capacity of the mix rGRA7 + rTgPF to initiate an immune response by evaluating dendritic cell activation. Both rTgPF and rGRA7 induces activation of mouse BMDCs more efficiently than the single proteins, evidenced by increased expression of CD80 and CD86 co-stimulatory proteins and secretion of IL-6, IL-10 and IL-12 cytokines after in vitro stimulation. The sum of the effects of rGRA7 and rTgPF on BMDCs maturation led us to assay them in a vaccination protocol. BALB/c mice vaccinated with this mix elicited a Th1-biased immunity via the induction of lymphocyte proliferation, activation of CD4+T cells and increased IFN-γ production that resulted in enhanced protection against chronic Toxoplama gondii infection. Profilin per se induce only cellular immunity but augments the effect of rGRA7 immune responses when used together, thus allowing us to postulate rTgPF as a potential adjuvant in a protein vaccine.

Published
2021
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8. Chronic infection with the protozoan Toxoplasma gondii prevents the development of experimental atopic dermatitis in mice

Author

Ignacio Martín Fenoy, Ariadna Soledad Soto, Mariano Sergio Picchio, Valentina Martin, Nadia Arcon, Silvia Vanzulli, María de los Angeles Aldirico, Alejandra Goldman, Rosalia Moretta, Vanesa Roxana Sánchez, and Matías D. Perrone Sibilia

Subjects
0301 basic medicine, Allergy, medicine.medical_treatment, Dermatology, medicine.disease_cause, Biochemistry, Dermatitis, Atopic, Allergic sensitization, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Allergen, medicine, Animals, Molecular Biology, Mice, Inbred BALB C, Innate immune system, biology, business.industry, Toxoplasma gondii, Atopic dermatitis, biology.organism_classification, medicine.disease, Chronic infection, 030104 developmental biology, Cytokine, Immunology, Chronic Disease, business, Toxoplasma, Toxoplasmosis
Abstract

Background Supporting the hypothesis thatT. gondii infection protects against allergy in humans we previously demonstrated that this infection can modulate not only the susceptibility to develop respiratory allergies in mice but also suppresses allergic responses at systemic level. This latter finding suggests that T. gondii infection could prevent the onset of other allergic diseases, such as atopic dermatitis. At present, few studies have investigated the modulation of atopic dermatitis by parasite infections. Objective Here, we sought to investigate whether chronic infection with T. gondii is capable of modulating the development of atopic dermatitis. Methods Chronically infected mice were sensitized by repeated epicutaneous ovalbumin administration. Skin histopathology, humoral response, cytokine production and innate type-II lymphoid cells (ILC2) were assessed. Results A marked reduction in epidermal thickness and dermal inflammatory infiltrate along with a reduction in mast cell count was observed in infected mice compared to non-infected mice. These results correlated with a diminished TH2 and TH1 allergen specific response. Reduced type-II IL-4 and IL-5 cytokines were already detected during the first 24 h of allergen sensitization in splenocytes and draining lymph nodes from infected mice. Moreover, this reduced type-II profile in chronically infected animals correlated with diminished ILC2 number in draining lymph nodes. Conclusion Chronic infection withT. gondii prevents the development of atopic dermatitis. The diminished susceptibility seems to result from changes in type-II innate immune response that may lead to the induction of a deficient TH2 response and consequently to a lower susceptibility to develop atopic dermatitis.

Published
2019

9. Genotyping of Toxoplasma gondii: The advantages of variable number tandem repeats within coding regions

Author

Rosalia Moretta, Valentina Martin, Vanesa Roxana Sánchez, Alejandra Goldman, Paula Ruybal, and Ignacio Martín Fenoy

Subjects
0301 basic medicine, Microbiology (medical), Genotyping Techniques, Minisatellite Repeat, 030106 microbiology, Minisatellite Repeats, Microbiology, Genome, 03 medical and health sciences, Tandem repeat, parasitic diseases, Genetic variation, Chlorocebus aethiops, Genetics, Animals, Molecular Biology, Genotyping, Vero Cells, Ecology, Evolution, Behavior and Systematics, Polymorphism, Genetic, biology, Toxoplasma gondii, Genetic Variation, biology.organism_classification, Variable number tandem repeat, 030104 developmental biology, Infectious Diseases, Genetic marker, Toxoplasma
Abstract

Toxoplasma gondii is an intracellular protozoan which is widely distributed. Infection occurs as a result of ingestion of uncooked meat and exposure to cat feces. Immunocompetent individuals are generally asymptomatic, while severe disease may occur in immunocompromised subjects and in congenital toxoplasmosis, which is caused by transplacental acquisition of T. gondii. Genetic diversity of T. gondii has often been studied using a PCR-RFLP scheme based on nine molecular markers. These studies led to the description of a clonal population structure with three main lineages (I, II and III) in North America and Europe and higher genetic diversity in South America. The aim of this study was to develop molecular markers that could allow the discrimination of genetic variants within each clonal lineage. We analyzed the genome of T. gondii to identify genes containing variable number tandem repeats (VNTRs). The coding sequences of T. gondii ME49 genome were processed with Tandem Repeat Finder software. A panel of candidate markers was selected based on the following parameters: the repeat unit size (>9 bp) and composition (to avoid single and dinucleotide runs), the number of copies (

Published
2017

10. Vaccine potential of antigen cocktails composed of recombinant Toxoplasma gondii TgPI-1, ROP2 and GRA4 proteins against chronic toxoplasmosis in C3H mice

Author

Mariano Sergio Picchio, Valentina Martin, Nadia Arcon, Alejandra Goldman, Vanesa Roxana Sánchez, Mariela Urrutia, María de los Angeles Aldirico, Rosalia Moretta, Ignacio Martín Fenoy, Matías D. Perrone Sibilia, and Ariadna Soledad Soto

Subjects
0301 basic medicine, Male, Protozoan Vaccines, 030106 microbiology, Immunology, Foreskin, Protozoan Proteins, Antibodies, Protozoan, Spleen, Antigens, Protozoan, Immunoglobulin G, Cell Line, 03 medical and health sciences, Mice, Immune system, Antigen, Intestinal mucosa, medicine, Animals, Humans, Intestinal Mucosa, Mice, Inbred C3H, Vaccines, Synthetic, biology, Toxoplasma gondii, Membrane Proteins, General Medicine, Fibroblasts, biology.organism_classification, medicine.disease, Toxoplasmosis, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Toxoplasmosis, Animal, Chronic Disease, Immunoglobulin A, Secretory, biology.protein, Cytokines, Parasitology, Female, Antibody, Toxoplasma
Abstract

The development of an effective and safe vaccine to prevent Toxoplasma gondii infection is an important aim due to the great clinical and economic impact of this parasitosis. We have previously demonstrated that immunization with the serine protease inhibitor-1 (TgPI-1) confers partial protection to C3H/HeN and C57BL/6 mice. In order to improve the level of protection, in this work, we combined this novel antigen with ROP2 and/or GRA4 recombinant proteins (rTgPI-1+rROP2, rTgPI-1+rGRA4, rTgPI-1+rROP2+rGRA4) to explore the best combination against chronic toxoplasmosis in C3H/HeN mice. All tested vaccine formulations, administered following a homologous prime-boost protocol that combines intradermal and intranasal routes, conferred partial protection as measured by the reduction of brain cyst burden following oral challenge with tissue cysts of Me49 T. gondii strain. The highest level of protection was achieved by the mixture of rTgPI-1 and rROP2 proteins with an average parasite burden reduction of 50% compared to the unvaccinated control group. The vaccine-induced protective effect was related to the elicitation of systemic cellular and humoral immune responses that included antigen-specific spleen cell proliferation, the release of Th1/Th2 cytokines, and the generation of antigen-specific antibodies in serum. Additionally, mucosal immune responses were also induced, characterized by secretion of antigen-specific IgA antibodies in intestinal lavages and specific mesenteric lymph node cell proliferation. Our results demonstrate that rTgPI-1+rROP2 antigens seem a promising mixture to be combined with other immunogenic proteins in a multiantigenic vaccine formulation against toxoplasmosis.

Published
2017

11. Plant heat shock protein 90 as carrier-adjuvant for immunization against a reporter antigen

Author

Ignacio Martín Fenoy, Marina Clemente, Mariana G. Corigliano, Alejandra Goldman, Valeria A. Sander, and Andrea Maglioco

Subjects
CIENCIAS MÉDICAS Y DE LA SALUD, Genes, MHC Class I, Tecnologías que involucran la identificación de ADN, proteínas y enzimas, y cómo influyen en el conjunto de enfermedades y mantenimiento del bienestar, CD8-Positive T-Lymphocytes, Plant Hsp90, Maltose-Binding Proteins, Biotecnología de la Salud, Interferon-gamma, Mice, Maltose-binding protein, Immune system, Adjuvants, Immunologic, Antigen, Tobacco, MHC class I, Splenocyte, Animals, Cytotoxic T cell, HSP90 Heat-Shock Proteins, Adjuvant, Plant Proteins, Immunity, Cellular, Mice, Inbred BALB C, General Veterinary, General Immunology and Microbiology, biology, Immunity, Public Health, Environmental and Occupational Health, Fusion protein, Molecular biology, Recombinant Proteins, Immunity, Humoral, Infectious Diseases, Immunoglobulin G, Immunology, biology.protein, Molecular Medicine, Female, Immunization, Vaccine, Spleen, CD8
Abstract

Here, we evaluated the modulation of the immune response induced by Hsp90 of Nicotiana benthami-ana (NbHsp90.3) against the Maltose Binding Protein (MBP) as a reporter antigen. Equimolar quantitiesof recombinant proteins were administered in mice as follows: MBP alone (MBP group), a mixture ofMBP and rNbHsp90.3 (MBP + rNbHsp90.3 group) and the fusion of MBP to rNbHsp90.3 (MBP-rNbHsp90.3group). The covalent linkage between NbHsp90.3 and MBP to bring a fusion protein was essential toinduce the strong specific antibody response with predominance of IgG2a. Eighty-four days after the firstimmunization, splenocyte proliferation from MBP-rNbHsp90.3-immunized mice was consistently higherthan that from MBP and MBP + rNbHsp90.3 groups. In addition, splenocytes from MBP-rNbHsp90.3 immu-nized mice produced higher levels of IFN- than controls. Finally, both formulations with rNbHsp90.3significantly enhanced the MHC class I expression levels, but only rNbHsp90.3 covalent bound to MBPinduced a specific cellular immune response against MBP measured as increased percentage of CD8+Tcells. Taken together, these results suggest that plant HSP90s could be incorporated as adjuvants in vac-cines that require the generation of a Th1 response along with a CD8 cytotoxic cell response to conferimmunity. Fil: Corigliano, Mariana Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina Fil: Fenoy, Ignacio Martín. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sander, Valeria Analía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina Fil: Maglioco, Andrea Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Goldman, Alejandra. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Clemente, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina

Published
2013
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12. Toxoplasma gondii serine-protease inhibitor-1: A new adjuvant candidate for asthma therapy

Author

Valentina Martin, Florencia March, Ignacio Martín Fenoy, Mariano Sergio Picchio, Fernando P. Polack, María de los Angeles Aldirico, Vanesa Roxana Sánchez, Ariadna Soledad Soto, Nadia Arcon, Alejandra Goldman, Patricio L. Acosta, and Matías D. Perrone Sibilia

Subjects
0301 basic medicine, Allergy, Pulmonology, Physiology, medicine.medical_treatment, Antibodies, Protozoan, lcsh:Medicine, Pathology and Laboratory Medicine, Immunoglobulin E, T-Lymphocytes, Regulatory, Biochemistry, Mice, White Blood Cells, 0302 clinical medicine, Antibody Specificity, Animal Cells, Immune Physiology, Allergies, Medicine and Health Sciences, Eosinophilia, Drug Interactions, ADJUVANT CANDIDATE, lcsh:Science, Immune Response, Mice, Inbred BALB C, Innate Immune System, SERIN PROTEASE INHIBITOR, Multidisciplinary, biology, T Cells, FOXP3, Forkhead Transcription Factors, Proteases, Animal Models, purl.org/becyt/ford/3.1 [https], respiratory system, Recombinant Proteins, Enzymes, Medicina Básica, medicine.anatomical_structure, Experimental Organism Systems, Cytokines, purl.org/becyt/ford/3 [https], Cellular Types, medicine.symptom, Toxoplasma, Research Article, CIENCIAS MÉDICAS Y DE LA SALUD, Serine Proteinase Inhibitors, Ovalbumin, Immune Cells, Inflammatory Diseases, T cell, Immunology, Inmunología, Mouse Models, Research and Analysis Methods, 03 medical and health sciences, Signs and Symptoms, Model Organisms, Diagnostic Medicine, medicine, Animals, IMMUNOTHERAPY, ASTHMA THERAPY, Cell Proliferation, Inflammation, Blood Cells, business.industry, lcsh:R, Biology and Life Sciences, Proteins, Cell Biology, Immunotherapy, Allergens, Molecular Development, medicine.disease, Asthma, 030104 developmental biology, 030228 respiratory system, Immune System, Enzymology, biology.protein, Clinical Immunology, lcsh:Q, Clinical Medicine, Serine Proteases, business, Developmental Biology
Abstract

Serine-proteases are important players in the pathogenesis of asthma, promoting inflammation and tissue remodeling. It’s also known that many serine protease inhibitors display immunomodulatory properties. TgPI-1 is a Toxoplasma gondii protein that exhibits broad spectrum inhibitory activity against serine proteases. In view of the increased prevalence of atopic disorders and the need to develop new treatment strategies we sought to investigate the potential of TgPI-1 for treating respiratory allergies. For this purpose, we developed a therapeutic experimental model. BALB/c mice were rendered allergic by intraperitoneal ovalbumin-alum sensitization and airway-challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with rTgPI-1 alone or with a mixture of rTgPI-1 and ovalbumin (OVA). A week later mice were given a secondary aerosol challenge. Treatment with rTgPI-1 alone or co-administered with OVA diminished bronchoalveolar eosinophilia, mucus production and peribronchial lung infiltration. This effect was accompanied by a lung resistance reduction of 26.3% and 50.3% respectively. Both treatments resulted in the production of lower levels of IL-4, IL-5, IFN-γ and regulatory IL-10 by thoracic lymph node cells stimulated with OVA. Interestingly, significant decreases in OVA specific IgE and T cell proliferation, and increases in FoxP3+ T cells at local and systemic levels were only detected when the inhibitor was administered along with OVA. These results show that both rTgPI-1 treatments reduced asthma hallmarks. However, co-administration of the inhibitor with the allergen was more effective. Hence, rTgPI-1 emerges as a novel adjuvant candidate for asthma treatment. Fil: Soto, Ariadna Soledad. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fenoy, Ignacio Martín. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sánchez, Vanesa Roxana. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Marchini, Florencia. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Perrone Sibilia, Matias. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Aldirico, María de Los Ángeles. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Picchio, Mariano Sergio. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Arcon, Nadia. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Acosta, Patricio Leandro. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; Argentina Fil: Martín, Valentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Goldman, Alejandra. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Published
2017

13. Toxoplasma gondii protease inhibitor-1 (TgPI-1) is a novel vaccine candidate against toxoplasmosis

Author

Anahí V. Fernández Cuppari, Alejandra Goldman, Bibiana Ledesma, Fernanda M. Frank, Sergio O. Angel, Valentina Martin, and Vanesa Roxana Sánchez

Subjects
Protozoan Vaccines, Genes, Protozoan, Protozoan Proteins, Antibodies, Protozoan, Antigens, Protozoan, Parasite load, Microbiology, Interferon-gamma, Mice, Immune system, Adjuvants, Immunologic, Antigen, medicine, Animals, Cells, Cultured, Mice, Inbred C3H, Innate immune system, General Veterinary, General Immunology and Microbiology, biology, Public Health, Environmental and Occupational Health, Toxoplasma gondii, biology.organism_classification, medicine.disease, Acquired immune system, Recombinant Proteins, Toxoplasmosis, Interleukin-10, Toxoplasmosis, Animal, Infectious Diseases, Immunoglobulin G, Toxoplasmosis, Cerebral, Immunology, biology.protein, Alum Compounds, Encephalitis, Molecular Medicine, Antibody, Toxoplasma
Abstract

The Toxoplasma gondii serin protease inhibitor-1 (TgPI-1) is a dense granule antigen that showed to specifically inhibit trypsin, chymotrypsin and neutrophil elastase, suggesting a possible modulatory role during the parasite invasion process and on the development of the innate immune response. To study the immune-protective value of TgPI-1, C3H/HeN mice were immunized with a recombinant form of the antigen rTgPI-1 combined with alum. All immunized mice produced specific anti-rTgPI-1 immunoglobulins, with high IgG antibody titers and a mixed IgG(1)/IgG(2a) response, with predominance of IgG(1) production. The cellular immune response was associated with the production of IFN-gamma and IL-10 cytokines. Vaccinated mice displayed significant protection against an oral challenge either after a lethal infection with Me49 cysts (90% survival vs. 50%) and also after a non-lethal infection (58% reduction in brain parasite load) compared to the non-vaccinated control group. In conclusion, rTgPI-1 elicits a strong specific immune response providing partial protection against both T. gondii acute and chronic infection, so it would be a good candidate in a vaccine against toxoplasmosis, which could be combined with other relevant parasite antigens.

Published
2008
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14. Homologous prime-boost strategy with TgPI-1 improves the immune response and protects highly susceptible mice against chronic Toxoplasma gondii infection

Author

Nadia Arcon, Vanesa Roxana Sánchez, Valentina Martin, Alejandra Goldman, Ignacio Martín Fenoy, Mariano Sergio Picchio, and Ariadna Soledad Soto

Subjects
Protozoan Vaccines, Adoptive cell transfer, CIENCIAS MÉDICAS Y DE LA SALUD, Injections, Subcutaneous, Veterinary (miscellaneous), Protozoan Proteins, Ciencias de la Salud, Biology, Drug Administration Schedule, Toxoplasma Gondii, Mice, Prime-Boost Strategy, Immune system, Serin Proteasa Inhibitor-1, Adjuvants, Immunologic, medicine, Animals, Mucosal Immunity, Parasitología, Immunity, Mucosal, Lymph node, Pathogen, Administration, Intranasal, Subunit Vaccine, Vaccination, Toxoplasma gondii, biology.organism_classification, Virology, Mice, Inbred C57BL, Chronic infection, Toxoplasmosis, Animal, Infectious Diseases, medicine.anatomical_structure, Insect Science, Immunology, Alum Compounds, Female, Parasitology, Nasal administration, Toxoplasma
Abstract

Subunit-based vaccines are safer than live or attenuated pathogen vaccines, although they are generally weak immunogens. Thus, proper combination of immunization strategies and adjuvants are needed to increase their efficacy. We have previously protected C3H/HeN mice from Toxoplasma gondii infection by immunization with the serine protease inhibitor-1 (TgPI-1) in combination with alum. In this work, we explore an original vaccination protocol that combines administration of recombinant TgPI-1 by intradermal and intranasal routes in order to enhance protection in the highly susceptible C57BL/6 strain. Mice primed intradermally with rTgPI-1 plus alum and boosted intranasally with rTgPI-1 plus CpG-ODN elicited a strong specific Th1/Th2 humoral response, along with a mucosal immune response characterized by specific-IgA in intestinal lavages. A positive cellular response of mesentheric lymph node cells and Th1/Th2 cytokine secretion in the ileon were also detected. When immunized mice were challenged with the cystogenic Me49 T. gondii strain, they displayed up to 62% reduction in brain parasite burden. Moreover, adoptive transfer of mesenteric lymph node cells from vaccinated to naïve mice induced significant protection against infection. These results demonstrate that this strategy that combines the administration of TgPI-1 by two different routes, intradermal priming and intranasal boost, improves protective immunity against T. gondii chronic infection in highly susceptible mice. Fil: Sánchez, Vanesa Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Fenoy, Ignacio Martín. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Picchio, Mariano Sergio. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Soto, Ariadna Soledad. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Arcon, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Golgman, Alejandra. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Martín, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina

Published
2015

15. Toxoplasma gondii infection modulate systemic allergic immune response in BALB/c mice

Author

Ariadna Soledad Soto, Ignacio Martín Fenoy, Vanesa Roxana Sánchez, Mariano Sergio Picchio, Valentina Martin, and Alejandra Goldman

Subjects
Allergy, CIENCIAS MÉDICAS Y DE LA SALUD, Immunology, Inmunología, Inflammation, medicine.disease_cause, TOXOPLASMA GONDII, Cell Degranulation, Allergic sensitization, Mice, Allergen, Immune system, parasitic diseases, INFECTION, medicine, Hypersensitivity, IMMUNE-MODULATION, Animals, Mast Cells, Lung, Sensitization, Cell Proliferation, Mice, Inbred BALB C, ANAPHYLAXIS, biology, Toxoplasma gondii, General Medicine, medicine.disease, biology.organism_classification, ALLERGY, Medicina Básica, Infectious Diseases, medicine.anatomical_structure, Toxoplasmosis, Animal, Cytokines, Parasitology, medicine.symptom, Toxoplasma, Anaphylaxis, Spleen
Abstract

The increased prevalence of allergies in developed countries has been attributed to a reduced exposure to some microbes. In agreement with epidemiological studies, we previously showed that Toxoplasma gondii infection prevents allergic airway inflammation. The mechanisms would be related to the strong Th1 response induced by the parasite and to regulatory cell induction. Herein we further characterized whether T. gondii allergy modulation extents to a systemic level or if it is limited to the lung. Parasite infection before allergic sensitization resulted in a diminished Th2 cytokine response and, when sensitized during acute infection, an increased in TGF-β production was detected. Allergen specific T cell proliferation was also reduced. Sensitization during both acute and chronic phases of infection resulted in a decreased anaphylaxis reaction. Our results extend earlier work and show that, in addition to lung airway inflammation, T. gondii infection can suppress allergic responses at systemic level. These results open the possibility that this protozoan infection could modulate other allergic disorders such as atopic dermatitis or oral allergies. Understanding the mechanisms by which different microorganisms regulate inflammation may potentially lead to the development of strategies aimed to control atopic diseases. Fil: Fenoy, Ignacio Martín. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sánchez, Vanesa Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Soto, Ariadna Soledad. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Picchio, Mariano Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Martín, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Goldman, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina

Published
2015

16. Regulatory cells induced by acute toxoplasmosis prevent the development of allergic lung inflammation

Author

Ignacio Martín Fenoy, Valentina Martin, Vanesa Roxana Sánchez, Mariana G. Corigliano, Andrea Maglioco, Graciela Dran, Alejandra Goldman, Mariano Sergio Picchio, and Ariadna Soledad Soto

Subjects
Allergy, CIENCIAS MÉDICAS Y DE LA SALUD, Immunology, Inmunología, Inflammation, T-Lymphocytes, Regulatory, TOXOPLASMA GONDII, Mice, Immune system, T-Lymphocyte Subsets, Respiratory Hypersensitivity, medicine, Animals, Humans, Immunology and Allergy, IMMUNE-MODULATION, Cells, Cultured, Sensitization, Cell Proliferation, Immunosuppression Therapy, Mice, Inbred BALB C, REGULATORY CELLS, biology, Toxoplasma gondii, FOXP3, Pneumonia, Hematology, purl.org/becyt/ford/3.1 [https], medicine.disease, biology.organism_classification, Adoptive Transfer, Toxoplasmosis, ALLERGY, Medicina Básica, Toxoplasmosis, Animal, medicine.anatomical_structure, Acute Disease, purl.org/becyt/ford/3 [https], IMMUNE SUPRESSION, medicine.symptom, Toxoplasma, Ex vivo, LUNG
Abstract

The increased prevalence of allergies in developed countries has been attributed to a reduction of some infections. Supporting epidemiological studies, we previously showed that both acute and chronic Toxoplasma gondii infection can diminish allergic airway inflammation in BALB/c mice. The mechanisms involved when sensitization occurs during acute phase would be related to the strong Th1 response induced by the parasite. Here, we further investigated the mechanisms involved in T. gondii allergy protection in mice sensitized during acute T. gondii infection. Adoptive transference assays and ex vivo co-cultures experiments showed that not only thoracic lymph node cells from infected and sensitized mice but also from non-sensitized infected animals diminished both allergic lung inflammation and the proliferation of effector T cells from allergic mice. This ability was found to be contact-independent and correlated with high levels of CD4+FoxP3+ cells. IL-10 would not be involved in allergy suppression since IL-10-deficient mice behaved similar to wild type mice. Our results extend earlier work and show that, in addition to immune deviation, acute T. gondii infection can suppress allergic airway inflammation through immune suppression. Fil: Fenoy, Ignacio Martín. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sánchez, Vanesa Roxana. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Soto, Ariadna Soledad. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Picchio, Mariano Sergio. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Maglioco, Andrea Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Corigliano, Mariana Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina Fil: Dran, Graciela Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Martín, Valentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Goldman, Alejandra. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Published
2014

17. Resistance of Very Young Mice to Inhaled Allergen Sensitization Is Overcome by Coexposure to an Air-Pollutant Aerosol

Author

Carroll-Ann W. Goldsmith, Lester Kobzik, Kaoru Hamada, and Alejandra Goldman

Subjects
Pulmonary and Respiratory Medicine, Ovalbumin, medicine.medical_treatment, Inflammation, Critical Care and Intensive Care Medicine, medicine.disease_cause, Coal Ash, Allergic sensitization, Mice, Allergen, Immune system, Administration, Inhalation, Respiratory Hypersensitivity, Animals, Medicine, Saline, Aerosolization, Asthma, Aerosols, Air Pollutants, Mice, Inbred BALB C, biology, business.industry, Allergens, respiratory system, medicine.disease, Carbon, Animals, Newborn, Immunology, biology.protein, Particulate Matter, medicine.symptom, business, Bronchoalveolar Lavage Fluid
Abstract

The role of air pollution in the initiation of asthma is controversial. We sought to model the potential effects of air pollution on immune responses to inhaled allergens in developing lungs by using very young mice. Neonatal mice were repeatedly exposed to aerosolized ovalbumin (OVA; 3% in phosphate-buffered saline for 10 min/d, from Days 5 to 15 of age). Some mice were also exposed to leachate of residual oil fly ash (ROFA-s), a surrogate for ambient air particles, for 30 min, on Days 6, 8, and 10 of age). Repeated exposure of very young mice to allergen alone (OVA) or pollutant alone (ROFA-s) had no effect on airway hyperresponsiveness (AHR, measured as enhanced pause (Penh) with noninvasive plethysmography at Day 16 of age), and did not cause inflammation or OVA-specific antibody production. Similar exposures of adult mice to either OVA alone or to OVA + ROFA-s did result in AHR, without evidence of enhancement by combined exposure. In contrast, very young mice exposed to both OVA and ROFA-s showed significantly increased AHR (e.g., Penh with 50 mg/ml methacholine for OVA + ROFA-s versus OVA alone = 2.6 +/- 0.4 [mean +/- SE], versus 1.2 +/- 0.1; p0.01, n/= 15), and produced OVA-specific IgE and IgG upon allergen challenge a week later. Immunostaining of airways taken from mice at Day 11 showed a marked increase in Ia(+) cells after OVA + ROFA-s exposure. We conclude that exposure to pollutant aerosols can disrupt normal resistance to sensitization to inhaled allergens, and can thereby promote development of airway hypersensitivity in this neonatal/juvenile mouse model.

Published
2000
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18. Combination of CpG-oligodeoxynucleotides with recombinant ROP2 or GRA4 proteins induces protective immunity against Toxoplasma gondii infection

Author

Valentina Martin, Ignacio Martín Fenoy, Martín N. Pitkowski, Alejandra Goldman, Anahí V. Fernández Cuppari, Facundo M. Rodríguez, Fernanda M. Frank, Ricardo S. Corral, and Vanesa Roxana Sánchez

Subjects
Protozoan Vaccines, CpG Oligodeoxynucleotide, medicine.medical_treatment, Immunology, Protozoan Proteins, Antibodies, Protozoan, Spleen, Microbiology, Mice, Antigen, Adjuvants, Immunologic, medicine, Animals, Mice, Inbred C3H, biology, Immunogenicity, Toxoplasma gondii, Brain, Membrane Proteins, hemic and immune systems, General Medicine, respiratory system, biology.organism_classification, Virology, Recombinant Proteins, Vaccination, Infectious Diseases, medicine.anatomical_structure, Toxoplasmosis, Animal, Oligodeoxyribonucleotides, biology.protein, Cytokines, Parasitology, Female, Antibody, Adjuvant, Toxoplasma
Abstract

Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) have been characterized as Th1-promoting immunopotentiators, an adjuvant activity desirable for vaccination against intracellular parasites like Toxoplasma gondii. In an attempt to find new antigen–adjuvant combinations that enhance the immunogenicity of antigen candidates for toxoplasma vaccines, we analyzed the extent of protection in mice immunized with ROP2 and GRA4 recombinant proteins when co-administered with CpG-ODN. Both GRA4 + CpG-ODN and ROP2 + CpG-ODN formulations were shown to induce a strong humoral Th1-biased response characterized by a high IgG2a to IgG1 antibody ratio. Both vaccination regimens led to increased secretion of IFN-γ and IL-10, and negligible amounts of IL-4, upon specific re-stimulation of spleen cells from these groups of mice. After a non-lethal challenge with tissue cysts of a moderately virulent strain, only the brains from mice vaccinated with ROP2 or GRA4 in combination with CpG-ODN showed a significant reduction (63% and 62%, respectively) in their parasite load compared to the controls. The rate of protection obtained with GRA4 + ROP2 + CpG-ODN resulted equivalent (66%) to those achieved with the single antigens plus CpG-ODN. Taken together, these results indicate that CpG-ODN is an important candidate adjuvant for use in potential multicomponent anti-T. gondii vaccines for animals and humans.

Published
2010

19. Toxoplasma gondii infection blocks the development of allergic airway inflammation in BALB/c mice

Author

I. Piazzon, E. Batalla, Fernanda M. Frank, Valentina Martin, Ignacio Martín Fenoy, M. Giovannoni, and Alejandra Goldman

Subjects
Allergy, CIENCIAS MÉDICAS Y DE LA SALUD, Ovalbumin, Immunology, Inmunología, TOXOPLASMA GONDII, Allergic inflammation, Allergic sensitization, Mice, Th2 Cells, Eosinophilia, parasitic diseases, medicine, Respiratory Hypersensitivity, Immunology and Allergy, Animals, Interleukin 5, Lung, Cells, Cultured, Mice, Inbred BALB C, biology, Toxoplasma gondii, purl.org/becyt/ford/3.1 [https], Eosinophil, respiratory system, Allergens, Immunoglobulin E, biology.organism_classification, medicine.disease, ALLERGY, Chronic infection, Medicina Básica, medicine.anatomical_structure, INFECTIONS, Immunoglobulin G, Acute Disease, Chronic Disease, Animal Studies, Cytokines, Female, purl.org/becyt/ford/3 [https], medicine.symptom, Bronchoalveolar Lavage Fluid, Toxoplasmosis, LUNG
Abstract

There is a link between increased allergy and a reduction of some infections in western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofaecal and foodborne microbes such as Toxoplasma gondii. Infection with T. gondii induces a strong cell-mediated immunity with a highly polarized T helper type 1 (Th1) response in early stages of infection. Using a well-known murine model of allergic lung inflammation, we sought to investigate whether T. gondii infection could modulate the susceptibility to develop respiratory allergies. Both acute and chronic infection with T. gondii before allergic sensitization resulted in a diminished allergic inflammation, as shown by a decrease in bronchoalveolar lavage (BAL) eosinophilia, mononuclear and eosinophil cell infiltration around airways and vessels and goblet cell hyperplasia. Low allergen-specific immunoglobulin (Ig)E and IgG1 and high levels of allergen-specific IgG2a serum antibodies were detected. A decreased interleukin (IL)-4 and IL-5 production by lymph node cells was observed, while no antigen-specific interferon-γ increase was detected. Higher levels of the regulatory cytokine IL-10 were found in BAL from infected mice. These results show that both acute and chronic parasite infection substantially blocked development of airway inflammation in adult BALB/c mice. Our results support the hypothesis that T. gondii infection contributes to protection against allergy in humans. © 2008 British Society for Immunology. Fil: Fenoy, Ignacio Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Giovannoni, M.. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Batalla, Estela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Martín, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Frank, Fernanda María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentina Fil: Piazzon, Margarita Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Leucemia Experimental; Argentina Fil: Goldman, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina

Published
2009
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20. Role of breast milk in a mouse model of maternal transmission of asthma susceptibility

Author

Lester Kobzik, Cedric Hubeau, Yasue Suzaki, Yuhong Xiang, Alejandra Goldman, Adriana S. Leme, and Kaoru Hamada

Subjects
Allergy, Offspring, Ovalbumin, Immunology, Gene Expression, Breast milk, Mice, Pregnancy, Risk Factors, Immunology and Allergy, Medicine, Animals, Humans, RNA, Messenger, Sensitization, Asthma, Mice, Inbred BALB C, Maternal Transmission, Base Sequence, Milk, Human, business.industry, Maternal effect, Infant, Newborn, respiratory system, Allergens, medicine.disease, respiratory tract diseases, Disease Models, Animal, medicine.anatomical_structure, Breast Feeding, Milk, Animals, Newborn, Cytokines, Methacholine, Female, Bronchial Hyperreactivity, business, Immunity, Maternally-Acquired, medicine.drug
Abstract

Epidemiologic data suggest a link between nursing by asthmatic mothers and increased risk of allergy in babies. We sought to experimentally test the potential contribution of breast milk mediator(s) in a mouse model of maternal transmission of asthma risk by evaluating the effect of adoptive nursing on asthma susceptibility in the offspring. We measured airway hyperresponsiveness (AHR) and allergic airway inflammation (AI) after an intentionally suboptimal OVA Ag sensitization, tested the allergen independence of the maternal effect by using a second allergen, casein, for sensitization of the baby mice, and tested the potential role of cytokines by measuring their levels in breast milk. Offspring of asthmatic, but not normal, mothers showed AHR and AI, indicating a maternal transfer of asthma risk. After adoptive nursing, both groups (litters born to asthmatic mothers and nursed by normal mothers, and normal babies nursed by asthmatic mothers) showed AHR (enhanced pause after methacholine aerosol, 50 mg/ml, 3.7 ± 0.7, 4.2 ± 0.5, respectively, vs 1.1 ± 0.1 normal controls, n = 25, p < 0.01) and AI, seen as eosinophilia on histology and bronchoalveolar lavage (40.7 ± 4.5%, 28.7 ± 3.7%, vs 1.0 ± 0.5% normals, n = 25, p < 0.01) after OVA sensitization. Similar results using casein allergen were observed. Multiplex assays for cytokines (IFN-γ, IL-2, IL-4, IL-5, TNF-α, and IL-13) in breast milk were negative. Breast milk is sufficient, but not necessary, to mediate allergen-independent maternal transmission of asthma risk to offspring.

Published
2006

21. Airway hyperresponsiveness caused by aerosol exposure to residual oil fly ash leachate in mice

Author

Carroll-Ann W. Goldsmith, Alejandra Goldman, Kaoru Hamada, Lester Kobzik, and Yasue Suzaki

Subjects
medicine.medical_specialty, Antioxidant, Ratón, Health, Toxicology and Mutagenesis, medicine.medical_treatment, Respiratory Tract Diseases, Industrial Waste, Inflammation, Incineration, Toxicology, Antioxidants, Mice, Internal medicine, Metals, Heavy, medicine, Animals, Respiratory system, Aerosols, Mice, Knockout, Air Pollutants, Inhalation Exposure, Lung, Chemistry, Antagonist, respiratory system, respiratory tract diseases, medicine.anatomical_structure, Endocrinology, Toxicity, Knockout mouse, Cytokines, medicine.symptom, Oils
Abstract

Particulate air pollution is associated with exacerbation of asthma and other respiratory disorders. This study sought to further characterize the pulmonary effects of residual oil fly ash (ROFA), an experimentally useful surrogate for combustion-derived particulates in ambient air. Mice were exposed to aerosols of the soluble leachate of residual oil fly ash (ROFA-s). Physiologic testing of airway function (non invasive plethysmography) showed increased Penh, an index of airway hyperresponsiveness (AHR), in a time- and dose-dependent manner after exposure to ROFA-s. BAL analysis showed a minor influx of neutrophils, which was maximal at 12 h after exposure and essentially resolved by the time point of maximal AHR (48 h after exposure). The AHR caused by ROFA-s was reproduced by a mixture of its major metal components (Ni, V, Zn, Co, Mn, Cu) but not by any individual metal alone. Systemic pretreatment of mice with the antioxidant dimethylthiourea abrogated ROFA-s-mediated AHR. Analysis of mice of varying ages showed that ROFA-s had no marked effect on airway responsiveness of 2-wk-old mice, in contrast to the AHR seen in 3- and 8-wk old mice. ROFA-s-mediated AHR was unchanged in neurokinin 1 receptor knockout mice and in mice treated with an neurokinin antagonist, arguing against a role for this mediator in ROFA-s-mediated effects. Data indicate that ROFA-s mediates AHR in mice through antioxidant-sensitive mechanisms that require multiple metal constituents. Maturational differences in susceptibility to ROFA-induced AHR may be useful for further studies of mechanisms of particle effects.

Published
2002

22. La educación como puente: Simmel, la tragedia de la cultura, y el desarrollo significativo del ser

Author

Marina Alejandra Goldman

Subjects
cultura, modernidad, tragedia, pedagogía, educación, Ethics, BJ1-1725, Political science, Philosophy (General), B1-5802
Abstract

Se debate la idea simmeliana de “tragedia de la cultura” en el marco de la relación entre cultura y vida en la modernidad. Complementariamente se indaga el potencial de la pedagogía escolar para, según Simmel, establecer un vínculo entre educación y cultura. Finalmente, se reflexiona sobre las deseables consecuencias que el establecimiento de este vínculo podría acarrear para el aplacamiento de la tragedia moderna descripta por el autor.

Published
2016

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