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Our immune system is essential for the protection against and destruction of pathogens, but also has an important role in cancer and tumor control. Therapy that is committed to use the immune system as anti-cancer strategy is called immunotherapy. Effective immunotherapy depends on the induction and activation of both innate (non-specific) and adaptive (specific and memory) immunity simultaneously combined with inhibition of tumor induced immune suppression. Vaccination, widely applied in the field of virology, can also be exploited in cancer to provide activation signals to the innate and adaptive immune players. Central players of innate and adaptive immunity that need to be instructed by vaccines are antigen presenting cells (APCs) such as dendritic cells (DCs) or Langerhans cells, which are both located in the skin, the prime vaccination site. APCs can be seen as messengers of the immune system that take up antigens, either tumor or pathogen derived, process and present them to T-cells that belong to the adaptive immunity and create specifity and memory. Stimulation of APCs facilitates their migration to lymph nodes where they can establish activation of innate immune cells, such as invariant natural killer T-cells (iNKT) in addition to activation of the adaptive immune response trough cross-presentation of antigens to CD8+ and CD4+ T-cells. These CD8+ and CD4+ T-cells can be respectively seen as effector cells that can kill tumor cells and helper cells that support CD8+ T-cells. iNKT can be described as immune boosters that aid in activation of both CD8+ and CD4+ T-cells, but also DCs and natural killer cells (which can kill tumor cells) but above all iNKT also exert killing capacities themselves. Since APCs play such a central role in the activation of antigen specific T-cell responses and iNKT, it is an attractive strategy to develop vaccines that are specifically delivered to APCs.
This comprehensive, authoritative treatise covers all aspects of mucosal vaccines including their development, mechanisms of action, molecular/cellular aspects, and practical applications. The contributing authors and editors of this one-of-a-kind book are very well known in their respective fields. Mucosal Vaccines is organized in a unique format in which basic, clinical, and practical aspects of the mucosal immune system for vaccine development are described and discussed. This project is endorsed by the Society for Mucosal Immunology. - Provides the latest views on mucosal vaccines - Applies basic principles to the development of new vaccines - Links basic, clinical, and practical aspects of mucosal vaccines to different infectious diseases - Unique and user-friendly organization
The most efficient way to mount a sustained immune response is to target antigens to antigen presenting cells that trigger both innate and adaptive immune responses. A comprehensive view of the current approaches to the design of new antigenic formulations will enhance our understanding and perspective of targeted immunotherapy. The aim of this Research Topic is to provide an overview of the currently adopted targeting strategies by a collection of articles on: 1.Novel approaches of antigen targeting for immunotherapeutic strategies against cancer and/or infectious diseases. 2. Diversity and biology of dendritic cell subsets in human and mouse. 3. Combined strategies for the delivery of antigens and adjuvant molecules that stimulate innate immune responses and their influence on the quality of immune responses. 4. Impact of the receptor mediate intracellular trafficking on antigen presentation.
Particle-based delivery of antigen has great potential for generating improved vaccines. During the course of an immune response, a pathogen may trigger multiple pattern-recognition receptors, instilling a strong proinflammatory immune response. Highly successful vaccines, such yellow fever vaccine and Dryvax® (smallpox), also induce immune responses by utilizing multiple pathogen-sensing signaling pathways, yielding long-lasting B and T cell responses. Subunit vaccines generally require an external adjuvant to boost immune responses; however, recent data has shown that targeting multiple immune activation pathways generates a more potent immune response, similar to native infection or immunization with live vaccines (Kasturi et al., 2011; Ahonen et al., 2004, 2008). To determine the effects of presenting targeting and/or activating moieties in a multivalent form, we generated two different particle-based vaccines. The first, an antigen-loaded, pH-sensitive hydrogel microparticle, was found to be taken up and presented by bone marrow-derived dendritic cells (BMDCs) in vitro and targeted to dendritic cells (DCs) and monocytes in vivo. Addition of targeting antibodies to the particle surface did not influence its uptake. DCs also upregulated activation markers when treated with microparticles, even when no agonistic anti-CD40 was conjugated to the microparticles. Furthermore, these particles induced increased percentages of interferon-[gamma]-producing CD8 T cells in response to challenge with a pathogen expressing the same antigen, in both an accelerated vaccination strategy using pre-loaded BMDCs and a traditional mouse immunization setting. The second particle, a luminescent porous silicon nanoparticle, displayed the same targeting and/or activating antibodies. This particle used antigen that was encoded in the 3' end of the targeting antibody instead of encapsulating it in the particle. Nanoparticles displaying agonistic anti-CD40 (with no antigen), produced a multivalent effect in B cells in vitro, in which the stimulatory effects of the CD40 nanoparticle were observed at 30-40-fold lower dose of antibody versus free anti-CD40. In vitro and in vivo, nanoparticles displaying targeting antibodies induced CD8 T cell proliferation better than those displaying control antibodies; however, this effect could not be consistently observed long-term in vivo, even with both targeting antibody and anti-CD40. In fact antigen-specific cells were most often deleted at memory time points.
Cancer remains a major challenge for modern society. Not only does cancer rank among the first three causes of mortality in most population groups but also the therapeutic options available for most tumor types are limited. The existing ones have limited efficacy, lack specificity and their administration carry major side effects. Hence the urgent need for novel cancer therapies. One of the most promising avenues in research is the use of specific immunotherapy. The notion that the immune system may have important anti-tumor effects has been around for more than a century now. Every major progress in microbiology and immunology has been immediately followed by attempts to apply the new knowledge to the treatment of cancer. Progress has reached a point where it is well established that most cancer patients mount specific T cell responses against their tumors. The molecular identity of the antigens recognized by anti-tumor T cells has been elucidated and several hundreds of tumor-derived antigenic peptides have been discovered. Upon recognition of such peptides presented by self MHC molecules, both CD8 and CD4 T cells are activated, expand to high numbers and differentiate into effective anti-tumor agents. CD8 T cells directly destroy tumor cells and can cause even large tumors to completely regress in experimental mouse models. These observations have spurred intense research activity aimed at designing and testing cancer vaccines. Over 100 years ago Coley successfully used intratumoral injection of killed bacteria to treat sarcomas. The important anti-tumor effects observed in a fraction of these patients fueled major research efforts. These led to major discoveries in the 80s and the 90s. It turns out that bacterial lipopolysaccharides stimulate the production of massive amounts of a cytokine still known today as tumor necrosis factor (TNF-a). They do so by engagement of a rather complex set of interactions culminating in the ligation of a Toll-like receptor, TLR -4. Ensuing signaling through this receptor initiates potent innate immune responses. Unfortunately the clinical use of both TNF-a and LPS can not be generalized due to their very narrow therapeutic margin. Importantly, synthetic Lipid A analogs have been identified that retain useful bioactivity and yet possess only mild toxicity. The relatively large body of information accumulated thus far on the molecular and cellular interactions set in motion by administration of LPS as well as by the synthetic lipid A analogs allow to place this family of bacterially-derived molecules at the crossroads between innate and adaptive immunity. By virtue of this key position, the therapeutic applications being pursued aim at using these compounds either as direct anti-tumor agents or as vaccine adjuvants. The clinical experience acquired so far on these two avenues is asymmetric. Few clinical trials using Lipid A analogs as single anti-cancer agents involving less than 100 patients with advanced cancer have been reported. In contrast, lipid A has been tested in over 300,000 individuals in various vaccines trials, including therapeutic cancer vaccines. Clearly most of the work needed to develop lipid A as effective anti-cancer agents and/or as vaccine adjuvant lies ahead in the near future. This book is a timely contribution and provides a much needed up-to-date overview of the chemical, biological and physiological aspects of lipid A. It should be a beacon to all those involved in this field of research.
Immunopotentiators in Modern Vaccines provides an in-depth insight and overview of a number of most promising immunopotentiators in modern vaccines. In contrast to existing books on the subject it provides recent data on the critical mechanisms governing the activity of vaccine adjuvants and delivery systems. Knowledge of immunological pathways and scenarios of the cells and molecules involved is described and depicted in comprehensive illustrations. - Contributions from leading international authorities in the field - Well-illustrated, informative figures present the interactions between immunopotentiators and the host immune system - Each chapter lists advantages and potential hurdles for achieving a practical application for the specific immunopentiator
This volume presents detailed laboratory protocols for in vitro synthesis of mRNA with favorable properties, its introduction into cells by a variety of techniques, and the measurement of physiological and clinical consequences such as protein replacement and cancer immunotherapy. Synthetic techniques are described for structural features in mRNA that provide investigational tools such as fluorescence emission, click chemistry, photo-chemical crosslinking, and that produce mRNA with increased stability in the cell, increased translational efficiency, and reduced activation of the innate immune response. Protocols are described for clinical applications such as large-scale transfection of dendritic cells, production of GMP-grade mRNA, redirecting T cell specificity, and use of molecular adjuvants for RNA vaccines. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Synthetic mRNA: Production, Introduction into Cells, and Physiological Consequences is a valuable and cutting-edge resource for both laboratory investigators and clinicians interested in this powerful and rapidly evolving technology.
Development of new-generation vaccines is now more challenging than ever, as identifying, purifying and evaluating vaccine antigens is a complex undertaking. Most importantly, once the relevant antigens have been identified, key focus then shifts to the development of suitable delivery systems and formulations to achieve maximum in vivo potency with minimum potential side effects. These novel formulations—many of which will be nanoparticulates—can deliver the antigens to the desired site, to the relevant antigen presenting cells, and prevent systemic exposure of the immune potentiators. The proposed book will outline all the critical steps that need to be considered for successful development of various types of nanoparticulate delivery systems for vaccine antigens. These contributions from leading experts in the area of vaccine formulation and delivery systems will tie in what is the most current status, including clinical evaluations with these novel vaccine technologies.​
Nanoscience or the science of the very small offers the pharmaceutical scientist a wealth of opportunities. By fabricating at the nanoscale, it is possible to exert unprecedented control on drug activity. This textbook will showcase a variety of nanosystems working from their design and construction to their application in the field of drug delivery. The book is intended for graduate students in drug delivery, physical and polymer chemistry, and applied pharmaceutical sciences courses that involve fundamental nanoscience. The purpose of the text is to present physicochemical and biomedical properties of synthetic polymers with an emphasis on their application in polymer therapeutics i.e., pharmaceutical nanosystems, drug delivery and biological performance. There are two main objectives of this text. The first is to provide advanced graduate students with knowledge of the principles of nanosystems and polymer science including synthesis, structure, and characterization of solution and solid state properties. The second is to describe the fundamentals of therapeutic applications of polymers in drug delivery, targeting, response modifiers as well as regulatory issues. The courses, often listed as Advanced Drug Delivery and Applied Pharmaceutics; Polymer Therapeutics; or Nanomedicine, are designed as an overview of the field specifically for graduate students in the Department of Pharmaceutical Sciences Graduate Programs. However, the course content may also be of interest for graduate students in related biomedical research programs. These courses generally include a discussion of the major principles of polymer science and fundamental concepts of application of polymers as modern therapeutics. All courses are moving away from the above mentioned course names and going by ‘pharmaceutical nanoscience or nanosystems’. This area of research and technology development has attracted tremendous attention during the last two decades and it is expected that it will continue to grow in importance. However, the area is just emerging and courses are limited but they are offered.
Immunization plays a key role in maintaining human health and each year, saves millions of lives from lethal pathogens and other fatal diseases in the most economical way, thanks to the advanced development of model vaccines. Subunit vaccines are regarded as a safer product than the whole microbe based-conventional vaccines and can be entrapped in various nanocarriers to form a vaccine adjuvant-delivery system (VADS) able to further boost their immunostimulatory activity. In this book, six groups of authors introduce immunization advances in VADSs designed for infection prophylaxis and cancer immunotherapy, problems and their resolution in both human and poultry immunization, and also, the mathematical model for assay of the basic immunization problem (BIP) understood from a finance point of view.