Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents, Vol. 4, No. 2, 2005
Contents
Innate
Immunity and Cytokines: How to Regulate Host Response Against Pathogens
Avoiding Autoreactivity
Guest
Editors: M.R. Zocchi and A. Poggi
Editorial
M.R.
Zocchi and A. Poggi
Triggering of Apoptosis and Pro-Inflammatory Cytokines in NK Cells: Regulation by Cyclosporin A Pp.115-120
Maria
Raffaella Zocchi and Alessandro Poggi
IFN-g: Detection and Prevention of Release Pp.121-131
Theresa
L. Whiteside
Control
of Interleukin-1b
Secretion in Inflammation and Immune Response Pp.133-140
Anna
Rubartelli
Danger-Detector
NKG2D: Immunosurveillance of Induced Self and Modulation by Cytokines and
Soluble Ligands Pp.141-152
K.
Wiemann and A. Steinle
Regulation
of Cytokine Production by gd T
Cells Pp.153-160
Daniela
Wesch, Lothar Marischen and Dieter Kabelitz
Mechanism
of Actions of Non Peptide Antigens Activating Human Vg9/Vd2 T
Lymphocytes and their Potential Use for Immunointervention Pp.161-168
Jean-Jacques
Fournie, Marc Bonneville and Francois Romagne
Regulation
of Dendritic Cell Function with Immunomodulatory Drugs Pp.169-175
M.
Mohty, B. Gaugler, N. Ben Mami and D. Olive
Immunomodulatory
and Anti-Viral Activities of Pertussis Toxin and of Its Non-Toxic Derivatives Pp.177-183
Massimo
Alfano and Guido Poli
Novel
Adjuvants for Vaccines Pp.185-191
Giampietro
Corradin and Giuseppe Del Giudice
General
Articles
Development
of New Immunotherapies for Japanese Cedar Pollinosis Pp.193-198
Masahiro
Sakaguchi and Kazuki Hirahara
The
Significance of COX-2 and COX-2 Inhibitors in Liver Fibrosis and Liver Cancer Pp.199-206
Jidong
Cheng and Toshikazu Hada
Abstracts
[Back
to top] Editorial
M.R. Zocchi and A. Poggi
From the immunological point of view, health can be defined as the results of the balance between host response against invading pathogens (bacteria, virures, fungi, parasites) and the control of autoimmune reactions. In particular, the immune response must undergo several passages involving different cell types, such as the effectors of the so-called natural or innate immunity (monocytes, granulocytes and natural killer, NK, cells), able to start the fight against foreign invaders, and the effctors of acquired immunity, such as ab and gd T lymphocytes, responsible for a more selective, antigen-specific reaction. In both cases the response must be self-limited, in order to avoid or limit tissue damage due to inflammation and/or autoimmunity. The correct progression of immuno-inflammatory responses depends on different intercellular communications for which cytokines function as major messengers. In this issue many aspects of this problem will be presented, from their involvement in the pathogenesis of infectious and autoimmune diseases to their potential role in diagnosis and therapy.
First, we discuss the importance of pro-inflammatory cytokines, such as IFNg, in NK cell function and focus on the role of an immunosuppressive drug, Cyclosporin A, in the regulation of inflammation which follows NK cell activation as in the case of the beginning of anti-viral responses, maintaining NK cell-dependent innate immunity (Poggi and Zocchi). As many human diseases are associated with aberrant production of IFN-g, including diseases caused by infectious agents, chronic inflammation, autoimmune diseases and cancer, there have been numerous attempts to measuring the kinetics of production and regulate synthesis and release of this cytokine. The review by Whiteside describes recent advances in technology that have provided us with excellent tools to dissect IFN-g regulatory pathways and profile its activity relative to other cytokines in the tissue microenvironment or inside cells. Furthermore, she analyzes the pharmacological and molecular approaches to control the biological activity of IFNg .
Blocking the function of other pro-inflammatory cytokines has been recently employed for treating autoimmune diseases. However, many cytokines including Interleukin (IL)-1, IL-18, HMGB1, belong to the family of “leaderless secretory proteins”, that leave the cells through pathways independent from the classical Endoplasmic Reticulum Golgi route, thus possibly escaping the conventional means of self regulation. The contribution by Rubartelli discusses the mechanisms underlying this peculiar type of secretion, pointing to possible pharmacological approaches aimed at controlling both release and activity of such cytokines (Rubartelli).
Gammadelta T cells are presented as a bridge between innate and acquired immunity, as exert a powerful activity against micobacteria, viruses and parasites exploiting biochemical characteristics of both NK cells and antigen-specific T lymphocytes. Two types of gd T cells exists: one bearing the Vd2 chain of T cell receptor represents a small fraction of circulating T lymphocytes, the other, expressing the Vd1 chain of T cell receptor, is confined to the mucosal associate lymphoid tissue. The different role played by these populations in the defense against microorganisms and the complex NK-like activity is discussed by Wiemann and Steinle, and the contribution by Wesch and Kabelitz focuses on the pattern of cytokine production and the possibility of regulating this function in the two cell subsets.
Furthermore, Vd2 T cells are selectively activated by non peptidic ligands that are in most instances phosphorylated. These phosphorylated compounds (also referred to as phosphoantigens) directly trigger Vg9/Vd2 T cell receptor-expressing cells, without need for MHC-restricted presentation molecules. Most of the known natural phosphoantigens are of microbial origin, and have been determined as low molecular weight components of a metabolic pathway, that can be modulated pharmacologically, specific for some microorganisms and parasites (Fournie, Bonneville and Romagne).
Going through the details of the immune system, Olive and coworkers deal with dendritic cells (DCs), which are specialized in the initiation of primary, antigen-specific immune responses. DCs are considered as important elements in the induction of specific antimicrobial or antiviral immune reactions and they play a pivotal role in linking innate and adaptive immunity. They serve as essential constituents of the immune system triggering immune reactions and are therefore considered as promising tools for immunotherapy.
Amplification of antigen-specific T cell responses against viruses can be potentiated with new vaccine amplifiers and new adjuvants. In this regard, some bacterial toxins possess immunostimulating properties that have been exploited in terms of vaccine adjuvancy and induction of specific cytotoxic T lymphocytes. Among these, Bordetella pertussis toxin (PTX) possesses the ability of modulating the immune responses in in vivo, ex-vivo and in vitro experimental systems. In the review by Alfano and Poli, the function of PTX, as well its nontoxic B-oligomer PTX-B and the genetically inactivated PT-9K/129G molecule, in controlling the infection of CD4+ T lymphocytes and macrophages by the human immunodeficiency virus, the etiological agent of the acquired immunodeficiency syndrome, is discussed. This article focuses on the regulation of the immune response and on the anti-viral properties of PTX and of its nontoxic related molecules and as an example of exploitation of a natural bacterial product to combat viral infections. Along this line, the review by Corradin and Del Giudice covers basic recent discoveries on the mechanism of action of adjuvants, which have been developed in the last decade. In particular, it focuses on the activation of TOLL like receptors and subsequent release of pro-inflammatory lymphokines (innate immunity), which, in turn, are thought to activate antigen specific responses (adaptive immunity).
In conclusion, both innate and acquired immune response can be regulated by conventional immunomodulating drugs and by known substances that are used in a novel way, or by small molecules that can function as vaccines or adjuvants. In any case, due to the complexity of the network that drives immune response against pathogens, it would be useful to design pharmacological agents targeted to selected biochemical processes involved in this response, in order to limit autoimmunity and avoid unwanted side effects.
[Back to top] Triggering of Apoptosis and
Pro-Inflammatory Cytokines in NK Cells: Regulation by Cyclosporin A
Maria
Raffaella Zocchi and Alessandro Poggi
Human natural killer (NK) cells are effectors of innate immunity, capable of killing transformed or virusinfected cells and producing pro-inflammatory cytokines, once activated in a non-HLA-dependent fashion. NK cells express receptors for HLA-I molecules, including CD8, or members of the Inhibitory Receptor Superfamily (IRS), such as the Killer Ig-like receptor (KIR) or C-Lectin type Inhibitory Receptor (CLIR). Soluble molecules of HLA-I (sHLA-I) are significantly increased in the serum of patients affected by auto-immune or infectious diseases.
We reported that upon interaction of sHLA-I with either CD8 or IRS activating isoforms (AR), NK cells produced and released FasL which elicited NK cell apoptosis by interacting with Fas at the NK cell surface. CD94/NKG2A or KIR2DL, both inhibiting isoforms of IRS, exerted an inhibitory effect on sHLA-I-mediated apoptosis and secretion of FasL induced via CD8, suggesting that IRS can function as survival receptors. Moreover, large amounts of IFN-g were detectable in culture supernatant of either CD8+ or AR+ NK cells incubated with the appropriate sHLA-I ligand. In chronic diseases, sHLA could amplify inflammation and, at the same time, eliminate effectors of innate immunity, thus favouring infections. On the other hand, this could represent a mechanism of down-regulation of NK-mediated functions as well, which ultimately contributes to limit self-reaction. Importantly, cyclosporin A (CsA) blocks both AR- or CD8-mediated apoptosis and IFN-g production, without affecting AR-mediated activation of cytolysis. This would indicate that CsA, although being an immunosuppressive drug, can downregulate inflammation maintaining NK cell-dependent innate immunity, further supporting CsA treatment in autoimmune diseases.
[Back to top] IFN-g: Detection and Prevention
of Release
Theresa
L. Whiteside
Interferon g (IFN-g) is a regulatory cytokine with a broad spectrum of biologic activities and considerable clinical importance. It is considered to be a master regulator of the immune system. Many human diseases, including infections, cancer and autoimmunity, are associated with aberrant production of IFN-g. Detection and regulation of IFN-g production is an important clinical objective. Today, levels of IFN-g in body fluids and tissues can be reproducibly measured by a variety of assays, including single-cell assays, that are discussed below. Strategies for inhibition of IFN-g secretion depend on immunologic, pharmacologic or genetic interventions. Increasingly, molecular approaches based on inhibition of IFN-g signaling pathways are considered for down-regulation of excessive IFN-g production in various pathologic conditions.
[Back to
top] Control of Interleukin-1b Secretion in Inflammation and Immune Response
Anna
Rubartelli
Intercellular communications are fundamental for a correct progression of immuno inflammatory responses. Major messengers in this network of information are cytokines, secretory proteins produced by immune and inflammatory cells. Blocking the function of pro-inflammatory cytokines has entered the clinical arena of treating autoimmune diseases. However, many cytokines including Interleukin (IL)-1, IL-18, HMGB1, belong to the family of “leaderless secretory proteins”, that leave the cells through pathways independent from the classical Endoplasmic Reticulum (ER)-Golgi route. Thus, a successful outcome of an approach aimed at inhibiting cytokine activity requires a clear definition of the mechanisms controlling their release. In this article we will review current hypotheses on the mechanisms underlying non classical secretion and discuss their implications in the regulation of the inflammatory and immune response. In particular, we will dissect the sequence of events required for IL-1b secretion and describe some members of the molecular machinery involved, which could provide novel targets whereby control of IL-1b production may be achieved.
[Back
to top] Danger-Detector NKG2D:
Immunosurveillance of Induced Self and Modulation by Cytokines and Soluble
Ligands
K.
Wiemann and A. Steinle
The novel “induced self” recognition mode mediated by the immunoreceptor NKG2D allows NK cells to eliminate dangerous and dysfunctional cells. Long-puzzling, complex NK cell reactivity patterns can now be explained – at least in part - by the combined action of the molecular players of the “missing self” and “induced self” hypotheses. Accordingly, MHC class I down-regulation in concert with an upregulated expression of self-ligands of activating NK receptors renders cells susceptible for NK cytotoxicity. The C-type lectin-like, activating NK receptor NKG2D detects a variety of inducibly expressed MHC class I-related molecules on stressed, infected, or malignant cells, and subsequently triggers effector functions of NK cells. Recent experiments also underline an important function of NKG2D on CD8 ab T cells in tumor immunosurveillance and in the pathogenesis of autoimmune diseases. Here, we review the current knowledge on NKG2D and its ligands (NKG2DL) with regard to their structure, expression, and function, refer to recent data on the involvement of NKG2D in anti-viral immune defence, tumor surveillance, and autoimmune phenomena, and outline emerging evidence on the modulation of NKG2D by cytokines and soluble NKG2DL.
[Back to top] Regulation of Cytokine
Production by gd T
Cells
Daniela
Wesch, Lothar Marischen and Dieter Kabelitz
A minority of peripheral blood T lymphocytes used heterodimeric T cell receptor (TCR) composed of a Vg9 chain associated with Vd2. These circulating Vg9Vd2 gd T cells mainly recognize low-molecular-mass non-peptide antigens derived from microbes and plants in a MHC-unrestricted manner. Furthermore, they produce rapidly after antigen contact cytotoxic molecules and cytokines, thereby activating innate immune cells, facilitating adaptive immune responses of ab T cells, protecting the host against infections with certain microbial pathogens, and playing a role in tumor defense. Another gd T cell subset underrepresented in the peripheral blood expresses Vd1 chain associated with variable Vg elements and comprises the major gd T cell population in epithelial tissues such as the small intestine. Homologous gd T cells are found in the mouse in vagina, uterus, lung and skin. Vd1 gd T cells mainly recognize antigens restricted to certain cell types of epithelial origin, which are induced upon stress, infection, inflammation and tumor growth, and thus play a role in immunosurveillance against malignancy, pathogen eradication, and wound healing. Several reports suggest that gd T cells are immunregulatory cells, interacting and modulating the activity of other immune cells directly or by cytokine production. Here we summarize the current knowledge on the role of cytokines produced by gd T cells and their ability to influence and regulate other cells of the immune system.
[Back
to top] Mechanism of Actions of Non
Peptide Antigens Activating Human Vg9/Vd2 T Lymphocytes and their Potential Use for
Immunointervention
Jean-Jacques
Fournie, Marc Bonneville and Francois Romagne
Human Vg9/Vd2 are a subset of gd T cells present only in non human primates and humans that have potent in vitro activities both on mycobacteria infected cells and on different cancer cell types. Their hallmark is that they are selectively activated by non peptidic ligands that are in most instances phosphorylated. These phosphorylated compounds (also referred to as phosphoantigens) directly trigger Vg9/Vd2 T cell receptor-expressing cells, without need for MHC-restricted presentation molecules. Most of the known natural phosphoantigens are of microbial origin, and have been determined as low molecular weight components of a metabolic pathway (DOXP, or non mevalonate) specific for some microorganisms and parasites. This pathway leads to the synthesis of farnesyl and genranyl disphosphate, precursors of sterols. Although the nature of tumor antigens recognized by Vg9/Vd2 T cells is still debated, recent data suggest that these are derived from the mevalonate pathway, which leads in most eukaryotic cells to the same geranyl and farnesyl diphosphate, also precursors of sterols, but also used for the farnesylation of proteins such as ras. The physiological significance of recognition of these metabolites by gd T cells will be discussed. Finally we will review several recent immunotherapeutic approaches targeting Vg9/Vd2 T cells, which rely on the use of several synthetic agonists or pharmacological inhibitors of the mevalonate pathway.
[Back
to top] Regulation of Dendritic Cell Function with
Immunomodulatory Drugs
M.
Mohty, B. Gaugler, N. Ben Mami and D. Olive
Dendritic cells (DC) represent a sentinel-like system with the capacity to capture and process antigens, to migrate into secondary lymphoid organs, and to activate naive T lymphocytes. DCs are considered as important elements in the induction of specific immune responses. The potency of DCs for induction of immune responses can be affected by a number of aspects related to their maturation stage and state of activation. For a long time, the critical role of DCs in many clinical situations was underscored. DCs in vivo might represent a favored target for immune tolerance (cancer) or immune activation (auto-immune diseases and allergic hypersensitivity). For immunotherapeutic applications, it is crucial to identify factors and agents that might affect the differentiation, maturation and function of DCs. This review will focus on the impact of the most widely used immunomodulatory drugs in the clinical setting on the properties and functions of DCs. The modulation and manipulation of DC functions through exposure of DCs to immunomodulatory agents both in vitro and in vivo is an approach that could result in therapeutic benefit in many clinical situations.
[Back
to top] Immunomodulatory and Anti-Viral Activities of
Pertussis Toxin and of Its Non-Toxic Derivatives
Massimo
Alfano and Guido Poli
The innate immune system represents the fastest defense to microbial invasion although many pathogens can modulate the host response either in favor of or against their survival and propagation. In this regard, some bacterial toxins possess immunostimulating properties that have been exploited in terms of vaccine adjuvancy and induction of specific cytotoxic T lymphocytes. Among these, Bordetella pertussis toxin (PTX) possesses the ability of modulating the immune responses in in vivo, ex-vivo and in vitro experimental systems. In addition, PTX, as well its nontoxic B-oligomer PTX-B and the genetically inactivated PT-9K/129G molecule, have been recently shown to inhibit infection of CD4+ T lymphocytes and macrophages by the human immunodeficiency virus, the etiological agent of the acquired immunodeficiency syndrome. This article focuses on the regulation of the immune response and on the anti-viral properties of PTX and of its nontoxic related molecules and as an example of exploitation of a natural bacterial product to combat viral infections.
[Back
to top] Novel Adjuvants for Vaccines
Giampietro
Corradin and Giuseppe Del Giudice
The review covers basic recent discoveries on the mechanism of action of adjuvants, which have been developed in the last decade. In particular, it focuses on the activation of TOLL like receptors and subsequent release of pro-inflammatory lymphokines (innate immunity), which, in turn, are thought to activate antigen specific responses (adaptive immunity). Given the number of novel adjuvants available to researchers, we limited the scope of the review to those adjuvants which are routinely used in our laboratories and of which we have first hand information.
[Back
to top] Development of New Immunotherapies for
Japanese Cedar Pollinosis
Masahiro
Sakaguchi and Kazuki Hirahara
We developed new immunotherapies (peptide and DNA vaccines) for treatment of Japanese cedar pollinosis. In the first place, oral administration of a dominant T cell epitope of a major Japanese cedar allergen (Cry j 2) in mice induced immunologic tolerance in both T-helper (Th) 1 and Th2 cell responses against the whole protein allergen. We found that peptide-based oral immunotherapy has a potential efficacy for treatment of the allergic immune response. Further, we developed a hybrid peptide comprising 7 T cell epitopes for human patients. It is expected that the hybrid peptide will downregulate allergen-specific T cells. We are planning a clinical study with the hybrid peptide in the near future. In the second place, we evaluated the use of DNA immunization by inoculating mice with plasmid DNA encoding a major Japanese cedar allergen (Cry j 1) gene. This DNA vaccination suppressed the IgE and IgG1 responses to subsequent alum-precipitated Cry j 1 injections. These results suggest that the DNA vaccination effectively induced Cry j 1-specific Th1-type immune responses, resulting in inhibition of the IgE responses to Cry j 1. Further, we developed DNA vaccine encoding both T cell epitope in Cry j 2 and invariant chain for the delivery of the epitope peptide into major histocompatibility complex (MHC) class II loading pathway. This DNA vaccination also suppressed the IgE responses to subsequent alum-precipitated Cry j 2 injections. DNA vaccine encoding T cell epitope and invariant chain induced epitope-specific T cell responses without allergic side effects.
[Back
to top] The Significance of COX-2 and COX-2
Inhibitors in Liver Fibrosis and Liver Cancer
Jidong
Cheng and Toshikazu Hada
Hepatitis, liver cirrhosis and liver cancer are major liver diseases particularly in Asia. Liver cancer is also one of the leading cancers causing death in the world. Cyclooxygenase 2 (COX-2) is a highly inducible and key rate-limiting enzyme involved in the production of prostaglandins (PGs), prostacyclin, and thromboxanes. COX-2 is expressed in response to a variety of proinflammatory agents and cytokines. COX-2 is associated with liver pathogenesis, including fibrosis and cancer. It has been shown that COX-2 is up-regulated in cirrhotic tissues adjacent to hepatocellular carcinoma (HCC) and well-differentiated HCC. We and others also observed the up-regulation of COX-2 in liver fibrosis. The chemopreventive efficacy of COX-2 inhibitors in liver fibrosis and hepato-carcinogenesis has been observed in animal experimental models. COX-2 inhibitors have also exhibited significant anti-proliferative effects on HCC cell lines by inducing apoptosis and cell cycle arrest and blocking growth signaling pathways. These results raise the possibility that COX-2 may be a target for the prevention or treatment of liver fibrosis, hepato-carcinogenesis and liver cancer, as it is for colon cancer. In this article, we review recent studies on the role of COX-2 in liver fibrosis and liver cancer, and discuss rationale and feasibility of COX-2 inhibitors in chemoprevention and treatment of liver fibrosis and liver cancer.