Inflammation & Allergy-Drug Targets (Discontinued) - Volume 10, Issue 5, 2011

We are happy to present in this issue of “Inflammation & Allergy - Drug Targets” under the guest editorship of Jean-Marc Sabatier a comprehensive series of outstanding articles - from molecules to clinics - of animal venoms with reference to allergic and immunological reactions and treatment options. We are fully aware that allergic or anaphylactic reactions to venoms in European latitudes mainly concerm wasps and bees and present only a niche of clinical and immunological research. However, for the Pacific Northwest, Central and Middle America, Asia, and Australia animal/insect venoms have a major implication for transferable diseases. Venoms and the concommitant transfer of pathogenic bacteria and virus by animal/insect bites often cause chronic or even deadly diseases due to rapid hemolysis, fibrinolysis, necrosis or neuronal disorders. At a time when pharmaceutical companies are having trouble finding new drugs and when biologicals are becoming more common, animal venoms could constitute an underexploited source of novel drug candidates. Desintegrins, for example, are low molecular weight peptides found in animal venoms of many snakes and have been recently used to inhibit cancer cell growth, adhesion, migration, invasion and angiogenesis [1, 2]. Furthermore, subcutaneous immunotherapy is the only effective treatment for patients who experience severe hymenoptera sting-induced allergic reactions; the treatment improves healthrelated quality of life, too [3]. It is interesting to know that now clinical application of approved drugs currently exists for the majority of snake venom proteins acting on haemostasis. The molecular diversity and mechanisms underlying animal venoms are at the beginning to be understood. The enormous potential that this resource represents for pharmacological prospects is at the arising horizon. Biomedical researchers, pharmacologists, clinicians and specialized biologists in animal/insect toxins must combine their efforts to reveal the active principle of animal/insect venoms in the development of new drugs to treat different disease and disorders, such as cancer, chronic inflammation or pain. As Editor-In-Chief, I would like to thank the guest editor Jean-Marc Sabatier for his excellent work to bring eminent experts from around the world together and who made it possible to publish this synopsis. I would like to thank them for submitting the papers which are now published after rigorous peer-reviewing. We also know, that, among leading journals in immunological niches, there is a high competition for excellent research papers; so, I also appreciate the firm belief of the authors in the high scientific quality of “Inflammation & Allergy - Drug Targets”. Therefore, we are looking forward for the dissemination of these published knowledges, above in those areas in the world where animal/insect venoms concern.....

The venoms from a variety of animal species (e.g. scorpions, snakes, spiders, sea anemones, marine cone snails, insects and worms) are rich sources of polypeptide toxins that often target -with high potency and variable specificity- different classes of ion channels. In recent years, a number of research teams have focused their efforts on studying the immunological responses to animal toxins. Apart from the vaccination viewpoint, the potential value of toxins (and related compounds) as immunomodulators and chemotherapeutic drugs to treat autoimmune diseases has been investigated, especially for some particular scorpion and sea anemone peptides acting on voltage-gated K+ channels (Kv1.3 channels), and intermediate conductance Ca2+-activated K+ channels (KCa3.1/IKCa1 channels). Indeed, T-cell lymphocytes reportedly express at their surface the Kv1.3 (and KCa3.1/IKCa1) channels that are required for antigen-induced cell activation; the same crucial role being also described for activation of B-cell lymphocytes that produce autoreactive antibodies. Therefore, such blockers -which have demonstrated their efficacies in vitro and/or in vivo (animal models)- might be good candidates in the treatment of either chronic graft rejection or other specific human diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, inflammatory myopathy, Crown and Hashimoto diseases, scleroderma, psoriasis, vitiligo, uveitis, erythemateous lupus, to cite a few. This special issue of ‘Inflammation & Allergy - Drug Targets’ deals not only with the functional aspects of animal toxins, but also with associated immune reactivity in the host, as well as the possibility to use venom molecules or derivatives in chemotherapeutic and prophylactic approaches. The eleven review articles have been written by the most distinguished toxinologists or immunologists, all of which have made major contributions in their respective areas of toxin research. The issue, which helps to better apprehend the complexity and potential of these compounds, finally covers the latest state of knowledge on (i) the pharmacology and immune properties of animal toxins, (ii) the effects of toxins related to immune reactions and cascades in the host, (iii) the toxins and derivatives as candidate chemotherapeutic drugs, (iv) the prophylactic approaches to animal venoms and toxins (candidate vaccines), (v) the prospects on management of immunity towards toxins, and (vi) the toxins as immunomodulators, from leads to effective drugs.

CCR7- effector memory T (TEM) lymphocytes are involved in autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus and rheumatoid arthritis. These cells express Kv1.3 potassium channels that play a major role in their activation. Blocking these channels preferentially inhibits the activation of CCR7- TEM cells, with little or no effects on CCR7+ naive and central memory T cells. Blockers of lymphocyte Kv1.3 channels therefore show considerable potential as therapeutics for autoimmune diseases. ShK, a 35-residue polypeptide isolated from the Caribbean sea anemone Stichodactyla helianthus, blocks Kv1.3 channels at picomolar concentrations. Although ShK was effective in treating rats with delayed type hypersensitivity and a model of multiple sclerosis, it lacks selectivity for Kv1.3 channels over closely-related Kv1 channels. Extensive mutagenesis studies combined with elucidation of the structure of ShK led to models of ShK docked with the channel. This knowledge was valuable in the development of new ShK analogs with improved selectivity and increasing stability, which have proven efficacious in preventing and/or treating animal models of delayed type hypersensitivity, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis without inducing generalized immunosuppression. They are currently undergoing further evaluation as potential immunomodulators for the treatment of autoimmune diseases.

Traditional healthcare systems in China, India, Greece and the Middle East have for centuries exploited venomous creatures as a resource for medicines. This review focuses on one class of pharmacologically active compounds from venom, namely peptide toxins that target ion channels. We highlight their therapeutic potential and the specific channels they target. The field of therapeutic application is vast, including pain, inflammation, cancer, neurological disorders, cardioprotection, and autoimmune diseases. One of these peptides is in clinical use, and many others are in various stages of pre-clinical and clinical development.

This review summarizes the key contributions to our knowledge regarding the immune response induced by snake venom toxins, focusing particularly on the production of antibodies and their venom-neutralizing effects. We cover the past and present state of the art of anti-snake venom production, followed by an overview of the venomous snakes and their venoms. The toxic properties of relevant snake venom toxins are approached in some details, with particular emphasis on the molecular domains responsible for binding to cells or plasma components in victims. The interactions of these domains are also reviewed, particularly the putatively relevant epitopes, along with the immune system and the resulting antibodies. We also review trials aimed at reducing the quantities of non-relevant antibodies in the antivenoms by substituting whole venoms with purified toxins to immunize animals, or the immunogenicity of the heterologous antivenom antibodies by humanizing their molecules.

Significant progress has been made in immunological studies of scorpion toxins and several formats of antibodies directed against scorpion toxins have been reported. Some of these are commonly used in a specific treatment against envenoming; others are primarily used for immuno-biochemical characterizations. The preparation protocol of the antibody or its fragments can be substantially different from one laboratory to another, which complicates a direct comparison of the potency of the antivenom. The use of immune sera, the total immunoglobulin fraction or Fab and Fab'2 fragments as the therapeutic agent is widespread. A number of monoclonal antibodies have also been reported and used for engineering of Fv, ScFv or Fab fragments. Recently, a novel antibody format - known as nanobodies - derived from HCAbs of camelids and selected after phage display shows great potential to provide a more efficient therapy against scorpion envenoming. Subsequent bispecific derivatives have been designed and their pharmacokinetics have been studied. Distinct advantages and disadvantages have been attributed to these equine, murine or camelid antibodies and their derived fragments. Some fragments are easily amenable into next generation therapeutics after proper manufacturing and provide an ensured availability of the product to the medical community. Through examples, we will show how the comparison of the serotherapeutic effectiveness is compromised due to the absence of standardization, on the preparation of immunogens, production processes and / or nature of the products. We will report on recent advances in the field.

Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. Antivenoms are manufactured by immunizing animals, usually horses, with venoms from a single or several medically-relevant snake species. Antivenoms are constituted by either whole IgG molecules or the immunoglobulin fragments F(ab')2 and Fab, obtained by digestion with pepsin and papain, respectively. Differences in the pharmacokinetics of these active substances have pharmacodynamic implications. Novel technological possibilities may improve the quality of antivenoms in the future, as well as their microbial safety. Antivenom administration might induce early and late adverse reactions, whose possible mechanisms are discussed. Owing to the large variety in the composition of snake venoms and to the need to demonstrate neutralization of relevant snake venoms in different countries, a meticulous preclinical and clinical assessment of antivenom efficacy and safety is required before an antivenom is introduced into clinical application. The accessibility of antivenoms in low-income tropical countries is of concern and efforts should be directed at guaranteeing the access of safe and effective antivenoms at affordable prices and their correct clinical use in these countries.

The immune response involves a complex repertoire of innate and adaptive responses to foreign agents in the organism. The present review focuses on the immune response to snake venoms, including those occurring in snakebite accidental envenomation, experimental vaccination and animal hyperimmunization for snake antivenom production. The following aspects are considered: (a) the structural characteristics of snake toxins and their relationship to immunogenicity, (b) the effects that factors such as administration route, venom dose, type of adjuvant, and individual and species characteristics of the immunized animal have on the immune response, (c) the initial venom-induced inflammatory response, (d) the process by which specific antibodies towards individual toxins are produced, and (e) the techniques currently used to evaluate the antibody response. Understanding the immune response to snake venoms is highly relevant for improving antivenom production and for gaining a more complete view of snakebite envenoming.

Venomous animals produce a diverse range of peptides and small molecules that are of both therapeutic and pharmacologic value. One such animal, the cone snail, produces peptides known as conotoxins, which may be of interest to those studying the mammalian immune system. Conotoxins are a family of venom peptides that display extraordinary diversity and often exquisite specificity for membrane protein targets, especially voltage and ligand activated ion channels. Conopeptides are proving to be important pharmacological tools to probe human physiology, with some showing promise as therapeutics for conditions such as neuropathic pain. The potential of these peptides to interact and modulate the human immune system has not been investigated despite literature suggesting that conotoxins could be valuable research tools and potential therapeutics in the area of immunology. Known pharmacological targets of conopeptides expressed by immunocompetent cells include voltage-gated potassium channel (Kv), voltage-gated calcium channel (Cav), nicotinic and acetylcholine receptors. In addition, the 5-HT3, GABAB and NMDA receptors that are not considered classic immunomodulators may play a secondary role in modulating immune responses. This review highlights venom peptides with the potential to act at immunological targets within the mammalian immune system.

Accidents involving venomous animals have always caught the attention of mankind due to their lethality and other clinical implications. However, since the molecules obtained from animal venoms have been the product of millions of years of evolutionary process, toxins could be used to probe physiological mechanisms and could serve as leads for drug development. The present work reviews the state of the art pertaining to venom molecules from Brazilian medically important arachnid species bearing potential biotechnological applications. Special focus is given to toxins isolated from the scorpion Tityus serrulatus and the spiders Phoneutria nigriventer and Lycosa erythrognatha, whose venoms possess molecules acting as erectile function modulators and as antihypertensive, analgesic, neuroprotective and antimicrobial agents.

Stings by insects of the order Hymenoptera cause systemic, sometimes life threatening allergic reactions in 1 - 5% of the population in Europe and North America. Responsible for these reactions is an IgE mediated sensitization to proteins of the venoms injected during the stings of social Hymenoptera species, mainly the honey bee (Apis mellifera), vespids like Vespula sp, Polistes sp. and ants, in southern US and central America Solenopsis invicta and in Australia Myrmecia pilosula. The venoms of these insects are composed of low molecular weight substances like biogenic amines, cytotoxic and neurotoxic peptides like melittin, apamin, MCD-peptide and mastoparan, and proteins, mostly enzymes like phospholipase A and hyaluronidase, which are major venom allergens. Immunotherapy with Hymenoptera venoms has been shown to protect 80 to over 95% of patients with a history of systemic allergic sting reaction from further systemic reactions after re-stings. The procedure, safety and efficacy of this treatment and the immune mechanisms involved are discussed. Since ancient times honey bee venom has been used for the treatment of chronic inflammatory disease, especially arthritis. Anti-inflammatory effects of bee venom have been documented in animal experiments. Most clinical studies suggest an antiinflammatory effect as well, but are uncontrolled. The only few controlled studies could not confirm efficacy of treatment with bee venom so far.

Cnidarians comprise four classes of toxic marine animals: Anthozoa, Cubozoa, Scyphozoa and Hydrozoa. They are the largest and probably the oldest phylum of toxic marine animals. Any contact with a cnidarian, especially the box jellyfish (Chironex fleckeri), can be fatal, but most cnidarians do not possess sufficiently strong venomous apparatus to penetrate the human skin, whereas others rarely come into contact with human beings. Only a small, almost negligible percentage of the vast wealth of cnidarian toxins has been studied in detail. Many polypeptide cnidarian toxins are immunogenic, and cross-reactivity between several jellyfish venoms has been reported. Cnidarians also possess components of innate immunity, and some of those components have been preserved in evolution. On the other hand, cnidarian toxins have already been used for the design of immunotoxins to treat cancer, whereas other cnidarian toxins can modulate the immune system in mammals, including man. This review will focus on a short overview of cnidarian toxins, on the innate immunity of cnidarians, and on the mode of action of cnidarian toxins which can modulate the immune system in mammals. Emphasis is palced on those toxins which block voltage activated potassium channels in the cells of the immune system

Just over a century ago, animal responses to injections of jellyfish extracts unveiled the phenomenon of anaphylaxis. Yet, until very recently, understanding of jellyfish sting toxicity has remained limited. Upon contact, jellyfish stinging cells discharge complex venoms, through thousands of barbed tubules, into the skin resulting in painful and, potentially, lethal envenomations. This review examines the immunological and toxinological responses to stings by prominent species of jellyfish including Physalia sp. (Portuguese Man-o-War, Blue-bottle), Cubozoan jellyfish including Chironex fleckeri, several Carybdeids including Carybdea arborifera and Alatina moseri, Linuche unguiculta (Thimble jellyfish), a jellyfish responsible for Irukandji syndrome (Carukia barnesi) and Pelagia noctiluca. Jellyfish venoms are composed of potent proteinaceous porins (cellular membrane pore-forming toxins), neurotoxic peptides, bioactive lipids and other small molecules whilst the tubules contain ancient collagens and chitins. We postulate that immunologically, both tubular structural and functional biopolymers as well as venom components can initiate innate, adaptive, as well as immediate and delayed hypersensitivity reactions that may be amenable to topical anti-inflammatory-immunomodifier therapy. The current challenge for immunotoxinologists is to deconstruct the actions of venom components to target therapeutic modalities for sting treatment.