Author: Shadi Swaidani Publisher: ISBN: Category : Asthma Languages : en Pages : 143
Book Description
Allergic asthma is a chronic inflammatory disorder of the lung and is characterized by dyspnea, wheezing, and cough due to episodes of bronchial inflammation and bronchoconstriction/airway hyperressponsiveness (AHR). Pathologically, asthma is manifested by an infiltration of CD4+ cells, neutrophils, eosinophils and mast cells, as well as smooth muscle and goblet cells hyperplasia, often associated with elevated serum IgE concentrations. The sensitization and progression towards allergic asthma are a result of reactivity of the airway epithelial cells and innate immune cells to allergens, and the subsequent induction of adaptive immunity. Antigen-induced allergic airway inflammation is mediated by CD4+ Th2 cells and their cytokines (IL-4, IL-5, IL-9 and IL-13). Recent studies have shown that IL-25 (also known as IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of Th2 responses. IL-25 is produced by airway epithelial cells, T lymphocytes of the CD4+ subset with a Th2 profile, and by innate effector eosinophils and basophils. However, the molecular mechanism for how IL-25 mediates Th2 immunity, remains elusive. We recently reported that Act1 is an essential signaling molecule for IL-25 receptor (IL-25R) signaling (Swaidani et al., 2009). We have also found that Act1 has E3 ubiquitin ligase activity and this function is critical for downstream signaling. Importantly, Act1 deficiency abolished IL-25-induced expression of IL-4, IL-5, IL-13, eotaxin-1 (CCL11), and pulmonary eosinophilia and resulted in diminished Th2 responses and less lung inflammation in a mouse model of allergic pulmonary inflammation. More specifically, Act1 deficiency in epithelial cells reduced both IL-25- induced eosinophilia, while Act1 deficiency in T cells resulted in diminished Th2 responses and less lung inflammation. Further, Act1 deficiency in the T cell compartment and not the epithelial compartment, resulted in an abrogation of allergic humoral and airway hyperresponsiveness (AHR). Based on these findings, we hypothesize that the IL-25 induced Act1-mediated signaling pathway plays an essential role in driving Th2 cell responses and allergic pulmonary inflammation through the differential impact on epithelial and T cell compartments.
Author: K. Izuhara Publisher: John Wiley & Sons ISBN: 1444346679 Category : Medical Languages : en Pages : 738
Book Description
Our knowledge and understanding of allergic diseases of the respiratory tract has improved to a point where new therapies are being developed for patient benefit. Inflammation and Allergy Drug Design explains the biologic science that underpins the pathophysiology of asthma and related disorders, as well as their mechanisms. This authoritative guide consists of 25 chapters, each detailing the cutting-edge developments in a particular field. It is divided into three parts, covering cytokines, chemokines, grow factors and mediators. This book allows immunologists, allergologists and researchers in the pharmaceutical industry to learn and appreciate the target biology in drug development. It also provides medical and pharmaceutical postgraduate students and clinicians with a basic understanding of allergic diseases in the respiratory tract.
Author: Peter D. Katsikis Publisher: Springer Science & Business Media ISBN: 1461462177 Category : Medical Languages : en Pages : 144
Book Description
This volume presents a collection of reviews derived from work presented at the Aegean Conference: “4th Crossroads between innate and adaptive immunity”. This meeting was the fourth in a series, and assembled a team of scientists working on mechanisms by which the innate immune system of the host senses pathogens, the cellular and signaling networks that orchestrate the innate response and antigen presentation and adaptive immunity. The importance of the crosstalk between innate immunity and the adaptive immune response has only recently started to be appreciated. Although it is well recognized that dendritic cells, NK cells, NK-T cells and T cells are all critical for the host response to pathogens, the respective fields that study the biology of these immune cells tend to exist in parallel worlds with minimum exchange of information and ideas. This fragmentation hinders the integration of these fields towards a unified theory of host response. The Aegean Conference “Crossroads between Innate and Adaptive Immunity” brought together leading international scientists and experts to address critical areas of Innate and Adaptive immunity something necessary for the development of more efficient scientific exchange and crosspollination between these fields. This conference attracted scientists from all over the world to discuss their latest findings on the various aspects of Innate and Adaptive immunity. The conference had limited participation and a scientific and social program that maximized scientific interchange through lecture presentations, poster sessions and informal discussions.
Author: Xun Zhang Publisher: ISBN: Category : Languages : en Pages :
Book Description
The complement anaphylatoxins (ATs) C3a and C5a are proinflammatory mediators contributing to the effector phase of allergic asthma. Recent studies suggest that ATs also play important immunoregulatory roles during allergen sensitization particularly at the interface of dendritic cells (DCs) and T cells. ATs exert their biological activities through interaction with three cognate receptors, namely the C3a receptor (C3aR), C5aR and C5a receptor-like 2 (C5L2). To investigate AT receptor-mediated regulation of pulmonary inflammation and maladaptive immunity, we have determined the immune responses in C3aR-, C5aR- and C5L2-deficient mice in models of house dust mite (HDM)- and ovalbumin (OVA)-induced experimental allergic asthma. Further, we directly examined the impact of AT receptor signaling in myeloid DCs (mDCs) on T cell activation and subsequent development of asthmatic phenotype. We found that HDM-treated C5aR-deficient mice (C5aRKOs) exhibited strong airway hyperresponsiveness (AHR), airway eosinophilia and dysregulated adaptive T and B cell responses, suggesting a protective immunoregulatory role for C5a in response to allergen exposure. Surprisingly, we observed that bone marrow-derived C5aR-deficient mDCs had an impaired ability to drive T helper type 2 (Th2) immunity, AHR and airway inflammation when adoptively transferred into the airways of naïve wild type (WT) mice. These data suggest that C5aR signaling in mDCs is required for efficient mDC function to activate naïve T cells and mediate allergen-induced inflammatory responses. Our findings further demonstrate that C5aR signaling in cell types other than mDCs accounts for its protective effect. Indeed, we found that C5aR signaling is required for pulmonary accumulation of tolerogenic plasmacytoid DCs expressing inhibitory B7-H1 and B7-DC molecules as a means to control Th2 cell effector functions. Contrary to C5aRKOs, C3aRKO and C5L2KO mice showed attenuated allergic phenotypes in response to inhaled allergens. Importantly, C5aR blockade in C3aRKOs resulted in a strong allergic phenotype similar to C5aRKOs. Further, we found reciprocal modulation of C5aR and C3aR in pulmonary DCs suggesting that C3aR signaling enhances the development of airway inflammation and maladaptive Th2 immunity indirectly through regulation of protective C5aR signaling. Interestingly, we observed that HDM-pulsed C3aR-deficient mDCs had the same potency as WT mDCs to drive Th2 immune responses, suggesting that C3aR signaling is not required for mDC-mediated activation of naïve T cells but important for proinflammatory effector functions mediated through infiltrating inflammatory cells during the allergic effector phase. In contrast, C5L2 and C5aR synergistically activated mDCs as evidenced by an impaired ability of C5L2-deficient mDCs to promote AHR, airway eosinophilia and B cell responses. Furthermore, we found a marked increase in pulmonary production of interferon-gamma and interleukin-17 associated with substantial airway neutrophilia in mice receiving C5aR- or C5L2-deficient mDCs, suggesting that C5a controls the differentiation of Th1 and Th17 cells as a potential mechanism to enhance Th2 cell development. In summary, our data presented in this thesis suggest that AT receptors exert critical and complex immunoregulatory functions that either promote or suppress the development of allergic asthma through regulation of DC-T cell interactions, effector cell and possibly pulmonary resident cell activities.
Author: Carlos Obed Medina Publisher: ISBN: Category : Languages : en Pages :
Book Description
Interleukin-10 (IL-10) is an anti-inflammatory cytokine with pleiotropic effects on antigen presentation, T-cell activation, and other immune phenotypes. IL-10 is a crucial regulator of immune responses, including those involved in type 2 allergic responses, autoimmunity, and inflammation-induced fibrosis. IL-10 is particularly important in allergic asthma, a common, debilitating disease that disproportionately affects children, minorities, and urban populations. Regulatory T cells, including Foxp3+ regulatory T cells (Treg) and type 1 regulatory T cells (Tr1), play a significant role in IL-10 production. These tolerogenic cell types have been proposed to contribute to immune tolerance in different, perhaps distinct contexts. However, while Foxp3+ Treg biology has been investigated extensively, Tr1 biology is relatively poorly understood. Recent efforts have sought to provide IL-10 exogenously or to induce human Tr1 cells for therapeutic treatment of allergic asthma and other disorders. However, these efforts are stymied by limitations in our understanding of Tr1 biology and the factors that govern IL-10 production. Extracellular matrix (ECM) molecules, including hyaluronan (HA) and heparan sulfate (HS), may modulate both Tr1 induction and IL-10 activity and provide a novel potential mechanism for enhancing existing Tr1 cell therapies. HA acts as a tissue integrity signal, capable of promoting homeostatic tolerance in its high molecular weight form or amplifying pro-inflammatory responses in its fragmented low molecular weight form. Heparin and HS can bind a number of soluble growth factors, chemokines, and cytokines, including IL-10, and modulate their activity in vitro and in vivo. In this thesis I have examined the cells and tissue ECM factors that influence Tr1 and IL-10 levels in the lung with an emphasis on allergic inflammation. Moreover, I present investigations into the impact of extracellular matrix molecules on tolerogenic cytokines and regulatory T cells. In Chapter 2, I describe my work characterizing the cells and kinetics involved in IL-10 production in a mouse model of allergic asthma. I report that Tr1 cell frequencies rise with inflammation and comprise the majority of the IL-10-producing cells at the peak of inflammation. These Tr1 cells are capable of forming antigen-specific tissue-resident memory but lose their inhibitory phenotype and propensity to produce IL-10 upon secondary challenge. Continual stimulation is required to maintain expression of the transcription factors Irf1 and Batf and consequent IL-10 production in memory Tr1 cells. This loss of IL-10 production in memory Tr1 cells suggests a critical need for novel approaches to maintain Tr1 phenotype long-term within tissue extracellular matrix. In Chapter 3, I describe the use of high molecular weight hyaluronan (HMW-HA) to promote the induction of IL-10-producing Tr1 cells and tolerance to airway allergens. We created a modified version of hyaluronan cross-linked to antigen, which we call XHA, which allows for the delivery of allergens in the context of anti-inflammatory co-stimulation. Intranasal administration of Ova-loaded XHA in previously sensitized mice reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and Th2 cytokine production. This inhibition was mediated by the suppressive effects of HA on dendritic cell maturation and was dependent on IL-10 production. Importantly, these effects were durable for weeks, providing an advantage over current desensitization protocols. In Chapter 4, I describe the therapeutic delivery of IL-10 using HA and HS hydrogels in a mouse model of bleomycin-induced fibrosis. The inclusion of HS facilitates the slow release of IL-10, prolonging its bioavailability and increasing its efficacy relative to IL-10 administered alone. This work highlights the anti-fibrotic effects of IL-10 and the potential for using ECM for delivering this. Chapter 5 focuses on the role of HS and the enzyme heparanase (HPSE) in regulatory T cell homeostasis. I report that Foxp3+ Treg use HPSE to access IL-2, a tolerogenic cytokine that promotes Treg survival, from the tissue ECM. These investigations highlight the importance of ECM factors in cytokine signaling and immune regulation. Finally, in Chapter 6, I describe the impact of a HS-mimetic, PG545, on lymphocyte polarization. I demonstrate that PG545 promotes Foxp3+ Treg polarization and can ameliorate allergic hypersensitivity in the skin. Together, these studies highlight crucial insights into IL-10 and regulatory T-cell mediated tolerance in airway inflammation. These studies open the door for further study into the roles and potential utilization of extracellular matrix and tissue-specific cues to promote the maintenance of airway tolerance.
Author: Patricia C. Fulkerson Publisher: ISBN: Category : Languages : en Pages : 295
Book Description
Airway inflammation in asthma is complex, involving innate and adaptive responses, pathologic Th2 sensitization, and alterations in tolerance. In this thesis, we aimed to characterize the contribution of chemokines, CCR3 signal transduction, and eosinophils to experimental asthma. Our studies, implicating the involvement of 17 chemokines in experimental asthma, highlight the complex interaction between numerous chemokines in the setting of allergic airway inflammation. We provide evidence for a murine eosinophil inhibitory pathway mediated by the chemokine CXCL9 (Mig) that potently blocks eosinophil chemoattraction and function by a mechanism dependent on CCR3 and Rac2. Our findings support a new paradigm whereby the major eosinophil chemokine receptor CCR3, previously identified solely as a powerful activating receptor in eosinophils, can transmit positive or negative signals depending upon the ligand engaged. We also demonstrate that eosinophil recruitment into the lung tissue is dependent on CCR3 in two different chronic experimental asthma models. In addition, we provide evidence that airway eosinophilia induced by IL-13 is CCR3- and eotaxin-2-dependent. Taken together, these results establish a regulatory chemokine network with the ability to inhibit or recruit particular leukocytes and localize the cells to specific target areas within a tissue utilizing the same chemokine receptor CCR3. To further define the relationship between allergic airway inflammation and the remodeling process, we induced chronic experimental asthma in mice with eosinophil recruitment defects. We reveal a critical role for CCR3 and eosinophils in allergen-induced mucus production and the orchestration of total leukocyte recruitment into the lung lumen. Importantly, we also demonstrate that CCR3-deficiency protects against methacholine-induced airway hyperresponsiveness. In addition, analysis of the reversibility of IL-13-induced chronic inflammation and lung remodeling revealed that while some aspects of chronic airway pathology are reversible (e.g. mucus cell metaplasia and lung eosinophilia), other important features remain or worsen during the repair process, providing compelling evidence that many of the prominent effects of IL-13 in the lung remain persistent following the initial pathological insult. Collectively, we provide evidence for a central role for CCR3 signal transduction and eosinophils in the development of multiple aspects of allergic airway disease.
Author: Silvia Beatriz Boscardin Publisher: Frontiers Media SA ISBN: 2889662012 Category : Medical Languages : en Pages : 511
Book Description
This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.
Author: Stephen P. Cobbold Publisher: Frontiers E-books ISBN: 2889190994 Category : Languages : en Pages : 233
Book Description
This Research Topic is a call for papers to provide an up to date assessment of current attempts to introduce tolerogenic therapies into clinical practice. Tolerance has been a highly sought after goal in the field of organ transplantation for over half a century, and is now readily achievable in rodent models, but considerable barriers remain to successfully translating tolerogenic treatments to the clinic. The initial call for this Research Topic has been aimed to provide an overview of recent advances made within the European RISET and American ITN networks with regard to tolerogenic strategies in clinical transplantation, autoimmune disease, and allergy. Articles will also cover the barriers to clinical tolerance induction and new emerging approaches to overcome such barriers. 1. Collaborative networks working towards the goal of therapeutic tolerance induction 2. Prope tolerance and minimization of immunosuppression 3. Lessons from operationally tolerant patients 4. Targeted withdrawal of immunosuppression 5. Stem cells and hematopoietic chimerism as a route to tolerance 6. Promoting regulatory T cells 7. Tolerogenic dendritic cells and negative vaccination 8. Inhibitory pathways and mechanisms in tolerance 9. Memory T cells and heterologous immunity 10. The innate response to allotransplants 11. Chronic graft loss--what are the missing links? 12. The impact of graft microenvironment on tolerance
Author: Shadi Swaidani
Author: Bartosz Stolarski
Author: K. Izuhara
Author: Peter D. Katsikis
Author: Xun Zhang
Author: Carlos Obed Medina
Author: Patricia C. Fulkerson
Author: Silvia Beatriz Boscardin
Author: Stephen P. Cobbold
Author: