Diets Supplemented with 1% Egg White Induce Oral Desensitization and Immune Tolerance in an Egg White-Specific Allergic Mouse Model

Allergic asthma is a chronic airway inflammatory response to different triggers like inhaled allergens. Excessive ATP in fluids from asthmatic patients is considered an inflammatory signal and an important autocrine/paracrine modulator of airway physiology. Here we investigated the deleterious effect of increased extracellular ATP (eATP) concentration on the mucociliary clearance (MCC) effectiveness and determined the role of ATP releasing channels during airway inflammation in an ovalbumin (OVA)-sensitized mouse model. Our allergic mouse model exhibited high levels of eATP measured in the tracheal fluid with a luciferin-luciferase assay and reduced MCC velocity determined by microspheres tracking in the trachea ex vivo. Addition of ATP had a dual effect on MCC, where lower ATP concentration (µM) increased microspheres velocity, while higher concentration (mM) transiently stopped microspheres movement. Also, an augmented ethidium bromide uptake by the allergic tracheal airway epithelium suggests an increase in ATP release channel functionality during inflammatory conditions. The use of carbenoxolone, a non-specific inhibitor of connexin and pannexin1channels reduced the eATP concentration in the allergic mouse tracheal fluid and dye uptake by the airway epithelium, providing evidence that these ATP release channels are facilitating the net flux of ATP to the lumen during airway inflammation. However, only the specific inhibition of pannexin1 with 10Panx peptide significantly reduced eATP in bronchoalveolar lavage and decreased airway hyperresponsiveness in OVA-allergic mouse model. These data provide evidence that blocking eATP may be a pharmacological alternative to be explored in rescue therapy during episodes of airflow restriction in asthmatic patients.

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Systemic And/Or Local Aerosol Inhibition Of S-Nitrosoglutathione Reductase (GSNOR) Ameliorates Physiologic, Biologic, And Proteomic Phenotypes In An Allergic Mouse Model Of Inflammatory Airway Disease

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a4075 ◽

2011 ◽

Author(s):

Loretta G. Que ◽

Matthew W. Foster ◽

Erin N. Potts ◽

Erik J. Soderblom ◽

Zhonghui Yang ◽

...

Keyword(s):

Mouse Model ◽

Airway Disease ◽

Inflammatory Airway Disease ◽

Allergic Mouse

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245. AAV2/8-Mediated Efficacy and Immune Tolerance in a Pompe Disease Mouse Model

Molecular Therapy ◽

10.1016/j.ymthe.2005.06.248 ◽

2005 ◽

Vol 11 ◽

pp. S96-S97

Keyword(s):

Mouse Model ◽

Immune Tolerance ◽

Pompe Disease

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Immunomodulatory Effects of Egg White Enzymatic Hydrolysates Containing Immunodominant Epitopes in a BALB/c Mouse Model of Egg Allergy

Journal of Agricultural and Food Chemistry ◽

10.1021/jf803372b ◽

2009 ◽

Vol 57 (6) ◽

pp. 2241-2248 ◽

Cited By ~ 32

Author(s):

Marie Yang ◽

Chengbo Yang ◽

Françoise Nau ◽

Maryvonne Pasco ◽

Lekh R. Juneja ◽

...

Keyword(s):

Mouse Model ◽

Egg White ◽

Egg Allergy ◽

Immunomodulatory Effects ◽

Enzymatic Hydrolysates ◽

Immunodominant Epitopes

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Molecular Determinants of Lymph Node Microenvironment Induced Host Immune Tolerance In CLL: Role for CAV1, PTPN6, and PKCβ In the Process

Blood ◽

10.1182/blood.v116.21.1367.1367 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1367-1367

Author(s):

Christine Gilling ◽

Amit Mittal ◽

Vincent Nganga ◽

Vicky Palmer ◽

Dennis D. Weisenburger ◽

...

Keyword(s):

Gene Expression ◽

Mouse Model ◽

Immune Tolerance ◽

Conflicts Of Interest ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Receptor ◽

Differentially Expressed ◽

Expression Levels ◽

Aggressive Disease

Abstract Abstract 1367 Previously, we have shown that gene expression profiles (GEP) of CLL cells from lymph nodes (LN), bone marrow (BM), and peripheral blood (PB) are significantly different from each other. Among the major pathways associated with differential gene expression, a “tolerogenic signature” involved in host immune tolerance is significant in regulating CLL progression. The genes associated with the tolerogenic signature are significantly differentially expressed in patient LN-CLL compared to BM-CLL and PB-CLL, suggesting that LN-CLL cells induce this immune tolerance. From 83 differentially expressed genes identified by GEP that are associated with immune dysregulation, we selected eleven genes (CAV1, PTPN6, PKCb, ZWINT, IL2Ra, CBLC, CDC42, ZNF175, ZNF264, IL10, and HLA-G) for validation studies to determine whether these genes are also dysregulated in the Emu-TCL1 mouse model of CLL. The results demonstrate a trend of upregulation of these genes as determined by qRT-PCR in the LN-tumor microenvironment. To further evaluate the kinetics of selected gene expression during tumor progression, we determined the expression levels of Cav1, Ptpn6, and Pkcb at 12, 24, and 36 weeks of CLL development in the Em-TCL1 mouse model. We found that the expression of all three genes increased as a function of age, indicating a correlation of gene expression with disease progression. In addition, as CLL progressed in these mice there was a marked decrease in CD4+ and CD8+ T cells. The murine data were further validated using CLL cells from the same patients with indolent versus aggressive disease indicating a similar trend in expression as CLL progressed (n=4). Furthermore, patient data analyzed by Kaplan Meier analyses of the expression levels of the selected genes indicated a significant association between down-regulation of PTPN6 (p=0.031) and up-regulation of ZWINT (p<0.001) with clinical outcome as determined by a shorter time to treatment (p<0.05). Functional analysis by knockdown of CAV1 and PKCb in primary patient CLL cells determined by MTT assay showed a decrease in proliferation following knockdown of these genes (p<0.005). Protein-interaction modeling revealed regulation of CAV1 and PTPN6 by one another. Additionally, the PTPN6 protein regulates B cell receptor (BCR) signaling and subsequently the BCR regulates PKCb. Therefore, these data from both mice and humans with CLL, argue that an aggressive disease phenotype is paralleled by expression of genes associated with immune suppression. In particular, evidence presented here suggests, dysregulation of CAV1, PTPN6, ZWINT, and PKCb expression promotes CLL progression. Disclosures: No relevant conflicts of interest to declare.

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Deciphering of CD4+ T Cell Subsets Involved in Maintenance and Break of Immune Tolerance in a Humanized Mouse Model That Is Immune Tolerant to Human FVII

Blood ◽

10.1182/blood.v118.21.2188.2188 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2188-2188

Author(s):

Christine Lenk ◽

Markus Pasztorek ◽

Markus Weiller ◽

Rafi Uddin Ahmad ◽

Hans Peter Schwarz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mouse Model ◽

Immune Tolerance ◽

Neutralizing Antibodies ◽

Subcutaneous Administration ◽

T Cell Subsets ◽

Regulatory Mechanisms ◽

Clonal Deletion ◽

Danger Signals

Abstract Abstract 2188 25%-30% of patients with hemophilia A develop neutralizing antibodies following replacement therapy with factor VIII (FVIII). These patients can be treated with factor VIIa (FVIIa) which triggers the extrinsic pathway of coagulation and thereby bypasses the requirement for FVIII. We developed a new mouse model that is transgenic for human FVII and expresses specific immune tolerance to native human FVIIa. We aim to investigate the immunological impact of modified FVIIa product candidates and to characterize their immunogenicity by analyzing emerging FVIIa-specific T cell responses. The new mouse model offers a unique opportunity to study central and peripheral immune regulatory mechanisms and the generation of immune responses by pro-inflammatory antigen-specific effector T cells (Teff). We hypothesized that FVIIa-specific Teff having escaped clonal deletion are present in the periphery and may be actively suppressed by FVIIa-specific regulatory T cells (Tregs). To study this hypothesis, we immunized mice with recombinant FVIIa (rFVIIa) with or without LPS, a well-described “danger signal” being able to break immune tolerance by stimulating the innate immune system. Intravenous or subcutaneous administration of rFVIIa alone did not elicit antibody responses and thus immune tolerance to rFVIIa was not broken. However, co-administration of rFVIIa and LPS resulted in a specific antibody response that was not isotypically restricted. To further analyze the mechanisms behind this break of specific immune tolerance, we characterized rFVIIa-specific T cells by the expression of CD154, a marker of antigen-specific T cells. Cytokine production and CD154 expression were assessed upon re-stimulation with rFVIIa. In contrast to mice that were immunized with rFVIIa only, we found increased numbers of rFVIIa-specific T cells in rFVIIa-LPS-treated mice displaying a stable, highly pro-inflammatory (IL-2+/IFN-g+) memory phenotype. These data could suggest that rFVIIa-specific Teff that escaped clonal deletion during induction of central immune tolerance, are present in the periphery of human FVII-transgenic mice. This would imply that rFVIIa-specific Teff could be actively suppressed by Tregs. This suppression could be overcome by danger signals like LPS. We currently study the regulatory mechanisms that maintain tolerance upon administration of FVIIa without LPS. We are approaching this question by correlating the characteristics of FVIIa-specific Teff and Treg responses under both tolerant and non-tolerant conditions. Ultimately, we aim to understand which danger signals have to be provided to break immune tolerance and how tolerance is regulated. Understanding these regulatory mechanisms will enable us to develop new therapeutic strategies and prevent conditions that lead to the induction of antibodies against drug products in patients. Disclosures: Lenk: Baxter BioScience: Employment. Pasztorek:Baxter BioScience: Employment. Weiller:Baxter BioScience: Employment. Ahmad:Baxter BioScience: Employment. Schwarz:Baxter BioScience: Employment. Scheiflinger:Baxter BioScience: Employment. Reipert:Baxter Innovations GmbH: Employment. de la Rosa:Baxter BioScience: Employment.

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