Current Drug Targets – Inflammation & Allergy, Vol. 4, No. 2, 2005
Regulation
of Pathogenetic Aspects of Allergic Diseases
Guest
Editor: Lydie Izakovicova Holla
Editorial
Pp-139-140
Lydie Izakovicova
Holla
NOS: Molecular Mechanisms, Clinical Aspects, Therapeutic
and Monitoring Approaches
Pp-141-149
Sergei A. Kharitonov
Arachidonic Acid Signaling in Pathogenesis of Allergy:
Therapeutic Implications Pp-151-155
Anna Serrano-Mollar
and Daniel Closa
The Role of b2-Adrenergic
Receptors in Inflammation and Allergy Pp-157-162
Brigita Sitkauskiene
and Raimundas Sakalauskas
Targeting Chemoattractant Receptors in Allergic
Inflammation Pp-163-167
Daniele D’Ambrosio
CD14 and Toll-Like Receptors: Potential Contribution of
Genetic Factors and Mechanisms to Inflammation and Allergy Pp-169-175
Ting-fan Leung, Nelson
L.S. Tang, Gary W.K. Wong and Tai-fai Fok
Matrix Metalloproteinase-9 and Airway Remodeling in
Asthma Pp-177-181
Hiroyuki
Ohbayashi, and Kaoru Shimokata
Controlling Autoimmunity by Modulating the Function of
Autoantigen-Specific T Cells
Guest Editor: Andrew D.
Weinberg
Editorial
Pp-183-183
Andrew D. Weinberg
Systemic Immunomodulation of Autoimmune Disease Using
MHC-Derived Recombinant TCR Ligands
Pp-185-193
Gregory G. Burrows
Modulation of TNF Receptor Family Members to Inhibit
Autoimmune Disease Pp-195-203
Andrew D. Weinberg and Ryan Montler
Therapeutic Blockade of TCR Signal Transduction and
Co-Stimulation in Autoimmune Disease
Pp-205-216
Laurence M. Howard, Adam P. Kohm, Carol L. Castaneda and Stephen D. Miller
TCR Peptide Vaccination in Multiple Sclerosis: Boosting a
Deficient Natural Regulatory Network that may Involve TCR-Specific CD4+CD25+
Treg Cells Pp-217-229
Arthur A. Vandenbark
Evidence that Pregnancy Specific Glycoproteins Regulate
T–Cell Function and Inflammatory Autoimmune Disease During Pregnancy Pp-231-237
Bruce F. Bebo, Jr., and Gabriela S. Dveksler
The Role of CD8+ T Cells in Multiple Sclerosis
and its Animal Models Pp-239-245
Joan Goverman, Antoine Perchellet and Eric S. Huseby
Mechanisms of Cell Signaling and Inflammation in
Alzheimer’s Disease Pp-247-256
Gilbert J. Ho, Roulla Drego, Edwin Hakimian and Eliezer Masliah
Inflammatory Mediators as Potential Therapeutic Targets
in the Spine Pp-257-266
Sally Roberts and Robin C. Butler
TH2 Cytokines and Associated Transcription Factors as
Therapeutic Targets in Asthma
Pp-267-270
Yutaka Nakamura and Makoto Hoshino
Abstracts
[Back to top] Editorial
Lydie Izakovicova
Holla
Allergic diseases have become a worldwide public health problem affecting millions of people. It is generally acknowledged that a widespread increase in the prevalence of allergy has occurred over the last 50 years, and especially the last 20 years. Therefore, valid predictions of predisposing factors for the development of allergic diseases are highly desirable since they provide possibilities for early preventive or interventional treatments of patients on high-risk. The expression of the allergic phenotype depends on two major factors – a genetic predisposition and the environmental interactions. Recent advances in genetics and molecular biology have provided an enormous amount of information on the molecular mechanisms of the genesis of allergic diseases, ushering in new paradigms for allergy drug development.
This special issue of Current Drug Targets – Inflammation & Allergy entitled “Regulation of pathogenetic aspects of allergic diseases” is focused on the key areas of the regulation of pathogenetic aspects of allergic diseases including imbalanced Th1/Th2 responses with alterations of the cytokine network, functions of b2-receptors, CD14 and Toll-like receptors and their alteration with responsiveness to therapeutic agents, altered prostaglandin and nitric oxide metabolisms and remodeling extracellular matrix by enzymes from matrix metalloproteinase family. This issue covers description of the structure of these substances and their genes, as well as methods for their study, results of genetic studies with the identification of the molecular targets and the relationship of this target to the allergic disorders. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of the allergic response regulation on prevention and therapeutic intervention of allergy are discussed.
This special issue consists of six review articles that highlight various topics in this field. The review by Dr. S. Kharitonov (National Heart and Lung Institute, Imperial College, UK) entitled “NOS: Molecular Mechanisms, Clinical Aspects, Therapeutic and Monitoring Approaches” discusses the potential role of NO modulators (NO synthase inhibitors and NO donors) in asthma and COPD. Nitric oxide (NO), a small, unstable, potentially toxic free radical gas produced during the metabolism of L-arginine by a class of enzymes known as nitric oxide synthase (NOS), has been implicated as an important biological messenger in a variety of biological functions. Pharmacological manipulation of NO levels or NO biosynthesis may prove to be an important strategy for the treatment of disorders related to abnormal NO production.
Arachidonic acid, a 20-carbon fatty acid containing four double bonds, is liberated from the phospolipids by phospholipase A2, due to activation by diverse stimuli and can be metabolized by different enzymatic pathways leading to the synthesis of potent inductors or modulators of inflammatory processes. The mini-review “Arachidonic Acid Signaling in Pathogenesis of Allergy: Therapeutic Implications” by Dr. A. Serrano-Mollar and D. Closa (Institut d’Investigacions Biomediques de Barcelona, Spain) summarizes several molecular aspects of these pathways and outlines the potential therapeutic purposes.
b2-adrenoreceptor agonists constitute the most important bronchodilator drugs used in the management of asthma and key role of b2-adrenoreceptor in airway relaxation is well known. Furthermore, it seems this receptor may participate in inflammation and allergy. The review entitled “The Role of b2-Adrenergic Receptors in Inflammation and Allergy” by Dr. B. Sitkauskiene and R. Sakalauskas (Kaunas Medical University Hospital, Lithuania) describes the current state of knowledge of actual role b2-adrenoreceptors in allergy, molecular biology and genetics of b2-adrenoreceptors and their pro- and anti-inflammatory roles.
The paper “Targeting Chemoattractant Receptors in Allergic Inflammation” by Dr. D. D’Ambrosio (BioXell S.p.A. Milano, Italy) provides an interesting mini-review into the role of the chemotactic cytokine receptors in allergic inflammation. Chemokine receptors are a subset of the seven transmembrane-spanning family, which mediate their effects through interaction with heterotrimeric G-proteins. The ligands are a structurally related set of proteins that are selectively expressed in certain disease settings. The authors discuss the cellular distribution of each receptor, the corresponding chemokine ligands, and importance of understanding the function of these receptors in allergic diseases.
The human Toll-like receptors (TLRs) comprise an important and interesting group of receptors that regulate pathogen-related responses, and play a key role in the amplification of inflammation. While several years ago only few researchers working in the field of allergy had heard of TLRs, today they seem to be everywhere and there is a good reason for it since signaling via these receptors may be responsible for driving the maturation of the immune system and some of the most promising treatments for allergic disease may work via TLRs. The review "CD14 and Toll-like Receptors: Potential Contribution of Genetic Factors and Mechanisms to Inflammation and Allergy" by Dr. Ting-fan Leung and co-workers (The Chinese University of Hong Kong, Prince of Wales Hospital, China) describes the functions of these pattern recognition receptors in innate and adaptive immunity, and view of results of genetic studies for CD14 and Toll-like receptors genes. Finally, the prospect of using immunomodulatory agents targeting on the innate immunity to treat or prevent allergic diseases is discussed.
Structural bronchial alterations are often observed in asthma and airway remodeling is partly due to an excess of extracellular matrix (ECM) deposition in the airway wall. Matrix metalloproteinases (MMPs) are major proteolytic enzymes that are involved in the normal ECM turnover. The paper by Dr. H. Ohbayashi and K. Shimokata (Internal Medicine, Tohno-Kousei Hospital, Japan) entitled “Matrix metalloproteinase-9 and airway remodeling in asthma” provides further evidence of the importance of matrix metalloproteinase-9, one of the most important MMPs in asthma. This review is focused mainly on the key role of MMP-9 in airway remodeling. The authors also discuss major cellular sources of MMP-9, the regulation of MMP-9 production and secretion and contribution of nitric oxide to MMP-9 in asthma.
Finally, I hope that the collection of these review articles featured in this special issue of Current Drug Targets – Inflammation & Allergy will serve as a useful reference for clinicians and basic scientists interested in exploring these topics in this rapidly evolving field of pathogenetic aspects of allergic diseases.
[Back to top] NOS: Molecular Mechanisms, Clinical Aspects, Therapeutic
and Monitoring Approaches
Sergei A. Kharitonov
Nitrosative stress and nitration of proteins in airway epithelium maybe responsible for steroid resistance in asthma and steroid ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD (for example, combination treatment with NOS inhibitors and corticosteroids). Here, the potential role of NO modulators (NO synthase inhibitors and NO donors) has been reviewed, which if are given on a regular basis may have clinical benefit in asthma and COPD.
[Back
to top] Arachidonic Acid Signaling in Pathogenesis of Allergy: Therapeutic
Implications
Anna Serrano-Mollar
and Daniel Closa
In recent years, significant progress has been made in understanding the involvement of pro-inflammatory lipidic mediators in the pathogenesis of allergic diseases. The most relevant lipidic mediator is arachidonic acid and its metabolites. Arachidonic acid is the precursor for biosynthesis of eicosanoids, potent mediators of inflammation that have been implicated in the pathogenesis of diverse disease processes. Eicosanoids are mainly synthesized by the action of cyclo-oxygenase (prostaglandin endoperoxide synthase) that generates prostaglandins and thromboxane, and 5-lipoxygenase, which leads to the production of leukotrienes. In addition, 12- and 15-lipoxygenase are found in mammalian systems. The activity of these enzymes results in the formation of different hydroxyeicosatetraenoic acids, but their functions in vivo have not been clearly established in normal or pathological states. Since several arachidonic acid metabolites clearly play an important role in allergic response, a substantial effort has been directed to understanding the cellular and molecular aspects of these pathways and their pharmacological modulation. This review summarizes some of these aspects based on our current knowledge of the involvement of arachidonic metabolism in the pathogenesis of allergic diseases and outlines the potential therapeutic opportunities that can result from the modulation of these metabolites.
[Back to top] The Role of b2-Adrenergic
Receptors in Inflammation and Allergy
Brigita Sitkauskiene
and Raimundas Sakalauskas
Essential role of b2-adrenoreceptor (b2AR) in airway relaxation is well established. Nevertheless, b2AR seems playing an actual role in allergy and inflammation. Interaction between b2AR and proinflamatory cytokines in airway smooth muscle has been revealed. Being located on proinflamatory cells, b2ARs may influence function of these cells in vivo. It was clear established, that stimulation of b2AR inhibits release of proinflamatory mediators from mast cells, influences T-cell growth and function, eosinophil survival and function, including GM-CSF- or PAF-induced degranulation. Stimulation of b2ARs, located on alveolar macrophages and epithelial cells, has ambiguity influence on their regulation and function, including phagocytosis and mediator secretion, in vivo. Vascular responses, resulting in inhibition of plasma exudation were confirmed, but modulation of sensory nerves via b2AR is not certain yet. b2AR-agonists are effective in treatment of immediate allergic reactions, but desensitisation of b2ARs on inflammatory cells may result in paradoxical effects, especially in asthma.
In summary, it is clear that b2ARs may play an anti-inflammatory role in vitro. Unfortunately, in vitro data have shown limited applicability in vivo; therefore further research in this field is required.
[Back to top] Targeting
Chemoattractant Receptors in Allergic Inflammation
Daniele D’Ambrosio
Asthma, atopic dermatitis, allergic rhinitis, which are amongst the most clinically relevant allergic disorders in industrialized countries affecting hundreds of millions of people world-wide, are characterized by tissue infiltration of Th2 cells, eosinophils, mast cells and basophils. Recruitment of these leukocyte subpopulations proceeds in response to specific chemotactic clues produced by tissue resident cells and is further amplified by incoming leukocytes. Over the last decade a number of receptors for chemokines and other chemoattractants have been identified on distinct leukocyte subpopulations participating to the pathogenesis of allergic inflammation. Preferential expression of discrete chemoattractant receptors on relevant cell types and their up-regulation in affected organs and animal models of allergic inflammation has helped to restrict the list of culprits. Although searching of the appropriate target for pharmacological intervention is still in progress, discrete chemoattractant receptors are already attracting a strong interest from the pharmaceutical industry. Here, we will review the most recent advances on the role that specific chemoattractant receptors play in the pathogenesis of allergic inflammation and will discuss emerging developments in this field.
[Back to top] CD14 and Toll-Like
Receptors: Potential Contribution of Genetic Factors and Mechanisms to
Inflammation and Allergy
Ting-fan Leung, Nelson L.S. Tang, Gary W.K. Wong and Tai-fai Fok
Innate and adaptive immune responses evolve as protective mechanisms against infectious microorganisms in humans. CD14 and toll-like receptors (TLRs) are examples of pattern recognition receptors that detect antigenic molecules on the surface of gram-positive (peptidoglycans, lipoteichoic acid) and gram-negative (lipopolysaccharide) bacteria. In vitro studies suggest that lipopolysaccharide is a potent inducer of interleukin-12 production that is mediated by both CD14 and TLR4. The associated increase in interferon-g steers our immune system away form the allergy-driven type-2 helper T cell phenotype. Epidemiological studies that shed light on the possible protective influences of natural microbial exposure on asthma and atopy development will be discussed. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may alter the susceptibility to develop atopic disorders and other complex human diseases. The findings of these genetic association studies will be presented. Although highly conserved across a wide range of species, innate immunity genes demonstrate considerable inter-ethnic variability predominantly in the form of single nucleotide polymorphisms. The frequencies of these polymorphisms in CD14 and TLR genes in different ethnic groups will be discussed. Genetic variation in these genes may also play a role in the development of other human diseases that have an inflammatory component. Lastly, the prospect of using immunomodulatory agents targeting on the innate immunity to treat or even prevent asthma and other allergic diseases will be discussed.
[Back to top] Matrix
Metalloproteinase-9 and Airway Remodeling in Asthma
Hiroyuki Ohbayashi, and Kaoru Shimokata
Airway remodeling is a major change responsible for irreversible asthmatic airflow restriction. The Th-2 cytokines-dominant eosinophilic inflammatory mechanism cannot fully explain the progressive subepithelial fibrosis and structural changes in the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are the key enzymes responsible for ECM degradation. MMPs are normally produced and secreted under the tight regulation of, at least, 3 different levels: the gene transcriptional level, the activation of the latent form of enzyme, and the inactivation by specific endogenous inhibitors.
In asthmatic condition, as shown by the large amount of accumulated evidence in this review, MMP-9 is the most relevant among the 23 kinds of human MMPs at present detected. Although the mechanism is still under investigation and not accurately known, the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 is considered a major theory to explain the progression of asthmatic airway remodeling. Various inflammatory cytokines including TGF beta and growth factors play a pivotal role in MMP-9 production and secretion.
This review mainly focuses upon the pivotal role of MMP-9 in airway remodeling, and also upon major cellular source of MMP-9 in asthma such as eosinophils, neutrophils, epithelial cells and alveolar macrophages. This review also refers to the partial contribution of nitric oxide to MMP-9 in asthma.
[Back to top] Editorial
Andrew D. Weinberg
It has been hypothesized that T cell recognition of a self-antigen in the periphery, can lead to autoimmunity by activating T cells through T cell receptor signaling. However, in order for optimal activation to occur a second signal, termed "co-stimulation", has to be delivered by antigen presenting cells to the T cells. Both the T cell receptor and co-stimulatory signals have been specific targets for therapeutic intervention in autoimmune disease. Strategies targeting both the T cell receptor and costimulation will be discussed in detail within the contents of these review articles (Burrows, Miller, and Vandenbark, for targeting TCR-dependent mechanisms; Weinberg and Miller targeting costimulatory molecules). In human autoimmune diseases, such as MS, RA, and inflammatory bowel disease, activated T cells are found within the inflammatory lesions. However, there has been no direct link between an "autoAg" and a specific T cell receptor that is responsible for the development and/or progression for most of these human diseases. Therefore, finding ways to target and suppress T cell-specific immune activation through mechanisms other than blocking, T cell recognition of autoAg will be discussed in 3 of the 6 reviews (Weinberg, Miller, and Bebo).
It has long been noted that for several human autoimmune disorders (e.g. RA, SLE, and MS), there is a large increase of female to male cases. In MS and SLE, the ratio is 10:1 female to male. Thus, sex hormones may influence Ag-specific T cell function during and/or after recognition of autoAg. It has also been noted that female patients with relapsing autoimmune disease have far fewer clinical episodes during pregnancy, again suggesting that sex hormones or pregnancy-specific proteins may suppress T cell specific autoimmune responses. Therefore, modulating sex hormones and the use of pregnancy specific proteins/hormones may have important therapeutic implications for future treatment of autoimmune disease. This subject will be reviewed in the article by Bebo.
The group of scientists that have been assembled to write these reviews have all worked with the autoimmune model experimental autoimmune encephalomyelitis (EAE), which is an animal model that mimics the clinical signs of MS. Therefore, the majority of these reviews will focus on discoveries made in the EAE model. Immunizing mice with myelin proteins in a strong immune adjuvant induces EAE, and the majority of autoAg specific T cell responses that have been studied to date are CD4 T cell responses. However, activated CD8 T cells are present in the spinal cord and brain lesions of multiple sclerosis patients, therefore, the final chapter of this issue will be devoted to autoantigen recognition of CD8 T cells and their destructive capabilities in autoimmune disease (Goverman).
[Back to top] Systemic
Immunomodulation of Autoimmune Disease Using MHC-Derived Recombinant TCR
Ligands
Gregory G. Burrows
Human autoimmune disease involves local activation of antigen-specific CD4+ T cells that produce inflammatory Th1 cytokines leading to the further recruitment and activation of lymphocytes and monocytes, resulting ultimately in the destruction of target tissue. Antigen presenting cells (APCs) initiate activation of CD4+ T cells in a multistep process that minimally involves co-ligation of the TCR and CD4 by the MHC class II/peptide complex and costimulation through additional T cell surface molecules such as CD28. Disruption of this highly orchestrated series of events can result in the direct modulation of CD4+ T cell behavior. The interaction between MHC and TCR holds unique promise as a focal point for therapeutic intervention in the pathology of CD4+ T cell-mediated diseases, and MHC class II-derived Recombinant TCR Ligands (“RTLs”) have emerged as a new class of therapeutics with potent clinical efficacy in a diverse set of animal models for multiple sclerosis. Here I review the systemic effect that RTL therapy has on the intact immune system and present an overview of a molecular mechanism by which RTL therapy could induce these systemic changes.
[Back to top]
Modulation of TNF
Receptor Family Members to Inhibit Autoimmune Disease
Andrew D. Weinberg and Ryan Montler
Certain members of the TNF-receptor family have shown proinflammatory function during immune activation and can be directly involved with the pathogenic effects observed during an autoimmune episode. The TNF-R family members summarized in this review includes: TNF-RI + II, OX40, and 4-1BB and they are expressed on a variety of leukocytes within the body. Studies within the last decade suggest that all of these proteins or their natural ligands can be targeted with various agents designed to diminish clinical signs of disease in autoimmune models. The data from the preclinical models specifically involving TNF-blockade have led to the development of clinical trials for patients with multiple sclerosis and rheumatoid arthritis. This review will chronicle the preclinical development of agents designed to inhibit OX40 and 4-1BB functions in autoimmunity and discuss relevant preclinical and clinical data associated with TNF-blockade.
[Back to top] Therapeutic Blockade
of TCR Signal Transduction and Co-Stimulation in Autoimmune Disease
Laurence M. Howard, Adam P. Kohm, Carol L. Castaneda and Stephen D. Miller
Autoimmune diseases are initiated and maintained by presentation of self antigen through complex interactions between different cells of the immune system. In most autoimmune disorders, autoantigen-specific responses are induced by the activation of specific T cells with self peptides displayed on activated antigen presenting cells (APCs). These T cells may then activate and drive B cell responses that either initiate or contribute to chronic disease pathogenesis. In order to activate the T cell, two signals are required: T cell receptor (TCR) engagement by autoantigen presented in the context of self MHC class II and costimulation (CD28-CD80/CD86 interactions). Feedback must also be provided to the APC through MHC class II engagement by the TCR and through costimulatory events controlling T cell differentiation and effector function (CD154-CD40 interactions, among others). With this in mind, numerous strategies have been developed to block the engagement and activation of self-reactive cells. We review and discuss recent progress in understanding the efficacy and underlying molecular mechanisms of three separate immunotherapeutic strategies targeting the TCR and costimulatory molecules: i) blocking TCR signaling (using non-mitogenic anti-CD3 monoclonal antibody); ii) blocking CD28 costimulation (anti-B7 monoclonal antibody blockade); and iii) blocking CD40 engagement on APCs (anti-CD154 monoclonal antibody blockade).
[Back to top] TCR Peptide
Vaccination in Multiple Sclerosis: Boosting a Deficient Natural Regulatory
Network that may Involve TCR-Specific CD4+CD25+ Treg Cells
Arthur A. Vandenbark
Vaccination with self peptides contained within T cell receptor (TCR) chains, expressed by pathogenic Th1 cells can induce a second set of regulatory T cells that can reverse paralysis in rodents with experimental encephalomyelitis, and similarly, may have the potential to regulate myelin-reactive Th1 cells in patients with multiple sclerosis (MS). In this review, we discuss our recent discovery that TCR-reactive T cells generally possess classical inhibitory activity associated with Treg cells. CD4+CD25+ TCR-reactive T cells can inhibit CD4+CD25- indicator cells stimulated with anti-CD3/anti-CD28 antibody in a dose-dependent and cell-contact-dependent manner. Additionally, CD4+CD25+ T cells from blood of healthy control donors have significant responses to a pool of discriminatory TCR peptides, including BV10S1P, BV19S20, BV13S7, BV12S2A2T, BV11S1A1T, BV21S3A1T, AV15S1, and BV12S1A1N1. Patients with MS have varying degrees of deficient responses to TCR peptides, and by association, a defect in Treg cell function as well. TCR peptide vaccination using a new tripeptide mixture emulsified in IFA produced strong T cell responses in 100% of MS recipients, a dramatic improvement over previous vaccines given i.d. in saline that induced TCR-reactive T cell responses in about 50% of recipients. Responders to vaccination had a tendency towards reduced MRI lesions, and an early indication of enhanced Treg activity mediated by TCR-reactive T cells that could provide suppression of target as well as bystander T cells. These data provide a strong foundation for future TCR vaccination studies that will critically test the ability of the tripeptide mixture to induce significantly enhanced Treg activity and possible clinical and MRI benefits in vivo.
[Back to top]
Evidence that
Pregnancy Specific Glycoproteins Regulate T–Cell Function and Inflammatory
Autoimmune Disease During Pregnancy
The capacity of the pregnancy state to regulate T-cell function is well documented. A consequence of this regulation is that many T-cell mediated autoimmune disorders, including multiple sclerosis (MS) are suppressed during pregnancy. The suppression of MS during pregnancy is more potent than the currently available treatments for this disease. Thus, the study of immunoregulatory factors of pregnancy could potentially result in the discovery of novel MS treatments. The regulation of T-cell function during pregnancy is likely the result of significant hormonal changes and may well involve immunoregulatory proteins derived from the placenta. Pregnancy specific glycoproteins (PSGs) are the most abundant placentally derived glycoproteins in the maternal serum. The levels of PSGs are highest during the third trimester of pregnancy, a time marked by the most profound suppression of MS disease attacks. Recent studies by our laboratories, and others, suggest that PSGs regulate T-cell function. We propose this regulation occurs by two distinct, but complementary mechanisms. PSGs may regulate T-cell function by (1) directly signaling tetraspanins present on the cell surface and by (2) regulating T-cell function indirectly through signaling of tetraspanins expressed by macrophages and dendritic cells. In this report, we will review evidence implicating PSGs as important immunoregulatory proteins and discuss our recent findings regarding the mechanisms by which PSGs regulate T-cell function.
[Back to top] The Role of CD8+
T Cells in Multiple Sclerosis and its Animal Models
Joan Goverman, Antoine Perchellet and Eric S. Huseby
The role of CD8+ T cells in multiple sclerosis (MS) and its animal models has been enigmatic. Most studies of MS have focused on the role of CD4+ Th1 T cells and many therapeutic strategies have been directed toward ameliorating the activity of this subset. Some of these strategies were effective in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS dependent on CD4+ T cells, but paradoxically have worsened disease in MS patients. A great deal of evidence suggests that CD8+ T cells contribute to the pathogenesis of MS and should be considered in designing therapies. CD8+ T cells outnumber CD4+ T cells in MS lesions, and both clonal expansion and enrichment of memory cells is preferentially seen in the CD8+ T cell subset in the brain and cerebrospinal fluid of MS patients. New animal models have been developed that employ myelin-specific CD8+ T cells to induce central nervous system autoimmunity. In a CD8+ T cell model targeting myelin basic protein, clinical signs and pathology distinct from CD4+ T cell-mediated disease were observed that exhibited similarities to some aspects of MS. These differences are consistent with distinct effector mechanisms employed by CD8+ and CD4+ T cells in mediating tissue damage and suggest a need to consider the activity of CD8+ T cells in drug design. This review will focus on our current understanding of the role of CD8+ T cells in MS and the new animal models that allow us to investigate further the pathogenicity of this subset.
[Back to top]
Mechanisms of Cell
Signaling and Inflammation in Alzheimer’s Disease
Gilbert J. Ho, Roulla Drego, Edwin Hakimian and Eliezer Masliah
Alzheimer’s disease, the most common neurodegenerative dementia in the elderly, affects cognition, behavior and functioning, and a prominent neuroinflammatory component likely contributes to disease pathogenesis. The epidemiology of AD has previously shown that NSAID use decreases the incidence of AD, and evidence from tissue culture, in vivo models, and Alzheimer brain tissue studies indicate that inflammation in AD is mediated by the production of proinflammatory molecules, leading to microglial activation and neuronal damage. Preliminary clinical drug trials of anti-inflammatory agents, such as indomethacin, suggest slowing of cognitive decline in AD, further supporting a role for inflammation. The basic mechanisms underlying the AD neuroinflammatory cascade, which might accelerate the development of AD neuropathology, are poorly understood, but several recent studies implicate a number of established signaling pathways in this process. Microglial activation might involve beta-amyloid binding and activation of cell surface immune and adhesion molecules such as CD45, CD40, CD36 and integrins, with the subsequent recruitment of Src family tyrosine kinases such as Fyn, Lyn and Syk kinases. ERK and MAPK pathways are then activated, which induces proinflammatory gene expression and leads to the production of cytokines and chemokines. These molecules may then contribute to synaptic pruning, damage and loss, while TNFa can induce neuronal apoptosis and injury. The production of interleukins and other cytokines and chemokines also may lead to microglial activation, astrogliosis, and further secretion of proinflammatory molecules and amyloid, thus perpetuating the cascade. Simultaneously, direct neuronal injury from amyloid-induced signaling also contributes to neurodegeneration. Of clinical relevance, components of these pathways may be suitable targets for therapeutic modulation in AD and for the development of novel disease-modifying anti-inflammatory therapy.
[Back to top] Inflammatory
Mediators as Potential Therapeutic Targets in the Spine
Sally Roberts, and Robin C. Butler
Inflammation plays a variable part in the pathogenesis of several spinal disorders. Ankylosing spondylitis is a chronic inflammatory arthropathy of the spine and rheumatoid arthritis, whilst affecting predominantly limb joints, also affects the cervical spine in a significant proportion of people. Inflammation is also involved in disorders such as disc herniation and sciatica, which have previously been thought of as being primarily mechanical or degenerative. Anti-inflammatory agents which have been shown to be effective elsewhere in the body are discussed in this review as possible therapeutic agents in the spine. As the inflammatory cascade and immunopathology of these conditions continue to be elucidated, it has become apparent that individual molecules may be potential targets for inactivation or down-regulation. Candidates include pro-inflammatory cytokines, such as TNF-a, cytokines, e.g. IL-1 and IL-15, or enzymes enhancing the inflammation pathway such as the cyclooxygenases. Hence treatments based on inactivation of these molecules by various mechanisms, including antibodies, receptor antagonists, enzyme inhibitors or gene therapy, are being introduced. However, the mode of action of a particular molecule can be complex and sometimes apparently contradictory. For example, TNF-a is known to play an important role in promoting inflammation by upregulating expression of cell adhesion molecules on endothelial cells and stimulating the production of reactive oxygen intermediates, nitric oxide and prostaglandins. However, it can also have an immunosuppressive and anti-inflammatory role after prolonged release. Therefore, although inhibitors of many of these molecules are now in clinical application and trials (many with promising results in rheumatoid arthritis), it is important to remain vigilant and monitor long-term outcomes particularly when these treatments are used in clinical syndromes with relatively poorly defined immunopathology such as spinal disorders.
[Back to top]
TH2 Cytokines and
Associated Transcription Factors as Therapeutic Targets in Asthma
Yutaka Nakamura, and Makoto Hoshino
The increasing levels of morbidity and mortality due to the rising prevalence of asthma and other allergic diseases have inspired investigations of several new molecular techniques to improve treatment. Recently, several preclinical studies have been published which utilize attributes or facets of DNA to address asthma therapy. These novel therapeutics include antisense oligonucleotides against TH2 cytokines and associated transcription factors. While no clinical experience has yet been reported for any of these areas of research in asthma, specific small molecule inhibitors of TH2 cell responses would be desirable for treatment of this chronic disease. Six transcription factors (c-Maf, NF-AT, NF-IL-6, AP-1, STAT-6 and GATA-3) have been implicated in the differentiation of TH2-type lymphocytes and therefore, in addition to TH2-type cytokines, represent therapeutic targets for asthma.
This review will focus on new research involving suppression of Th2-type cytokines and associated transcription factors using antisense and decoy oligonucleotides. Recently, novel oligonucleotides have been devised to improve stability in vitro and in vivo stability against nucleases, and the efficacy of these approaches will also be presented.