Anthony E. Gregory

Bio: Anthony E. Gregory is an academic researcher from Texas A&M University. The author has contributed to research in topics: Vaccination & Coxiella burnetii. The author has an hindex of 7, co-authored 15 publications receiving 601 citations. Previous affiliations of Anthony E. Gregory include University of California, Irvine & Texas A&M Health Science Center.

Vaccine delivery using nanoparticles

Abstract: Vaccination has had a major impact on the control of infectious diseases. However, there are still many infectious diseases for which the development of an effective vaccine has been elusive. In many cases the failure to devise vaccines is a consequence of the inability of vaccine candidates to evoke appropriate immune responses. This is especially true where cellular immunity is required for protective immunity and this problem is compounded by the move toward devising sub-unit vaccines. Over the past decade nanoscale size (<1000 nm) materials such as virus-like particles, liposomes, ISCOMs, polymeric, and non-degradable nanospheres have received attention as potential delivery vehicles for vaccine antigens which can both stabilize vaccine antigens and act as adjuvants. Importantly, some of these nanoparticles (NPs) are able to enter antigen-presenting cells by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular pathogens. Their properties also make them suitable for the delivery of antigens at mucosal surfaces and for intradermal administration. In this review we compare the utilities of different NP systems for the delivery of sub-unit vaccines and evaluate the potential of these delivery systems for the development of new vaccines against a range of pathogens.

Use of Reverse Vaccinology in the Design and Construction of Nanoglycoconjugate Vaccines against Burkholderia pseudomallei.

Abstract: Burkholderia pseudomallei is a Gram-negative, facultative intracellular pathogen that causes the disease melioidosis in humans and other mammals. Respiratory infection with B. pseudomallei leads to a fulminant and often fatal disease. It has previously been shown that glycoconjugate vaccines can provide significant protection against lethal challenge; however, the limited number of known Burkholderia antigens has slowed progress toward vaccine development. The objective of this study was to identify novel antigens and evaluate their protective capacity when incorporated into a nanoglycoconjugate vaccine platform. First, an in silico approach to identify antigens with strong predicted immunogenicity was developed. Protein candidates were screened and ranked according to predicted subcellular localization, transmembrane domains, adhesive properties, and ability to interact with major histocompatibility complex (MHC) class I and class II. From these in silico predictions, we identified seven "high priority" proteins that demonstrated seroreactivity with anti-B. pseudomallei murine sera and convalescent human melioidosis sera, providing validation of our methods. Two novel proteins, together with Hcp1, were linked to lipopolysaccharide (LPS) and incorporated with the surface of a gold nanoparticle (AuNP). Animals receiving AuNP glycoconjugate vaccines generated high protein- and polysaccharide-specific antibody titers. Importantly, immunized animals receiving the AuNP-FlgL-LPS alone or as a combination demonstrated up to 100% survival and reduced lung colonization following a lethal challenge with B. pseudomallei Together, this study provides a rational approach to vaccine design that can be adapted for other complex pathogens and provides a rationale for further preclinical testing of AuNP glycoconjugate in animal models of infection.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Dependence of Nanoparticle Toxicity on Their Physical and Chemical Properties.

Abstract: Studies on the methods of nanoparticle (NP) synthesis, analysis of their characteristics, and exploration of new fields of their applications are at the forefront of modern nanotechnology. The possibility of engineering water-soluble NPs has paved the way to their use in various basic and applied biomedical researches. At present, NPs are used in diagnosis for imaging of numerous molecular markers of genetic and autoimmune diseases, malignant tumors, and many other disorders. NPs are also used for targeted delivery of drugs to tissues and organs, with controllable parameters of drug release and accumulation. In addition, there are examples of the use of NPs as active components, e.g., photosensitizers in photodynamic therapy and in hyperthermic tumor destruction through NP incorporation and heating. However, a high toxicity of NPs for living organisms is a strong limiting factor that hinders their use in vivo. Current studies on toxic effects of NPs aimed at identifying the targets and mechanisms of their harmful effects are carried out in cell culture models; studies on the patterns of NP transport, accumulation, degradation, and elimination, in animal models. This review systematizes and summarizes available data on how the mechanisms of NP toxicity for living systems are related to their physical and chemical properties.

Synthetic Nanoparticles for Vaccines and Immunotherapy

Abstract: 1.1 Progress and challenges in the new age of engineering immunity The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspective. 1.1.1 Key cellular actors in the immune system A brief summary of the cellular players in the immune response is worthwhile to preface the many immunomodulatory approaches described in this review. The immune system can be viewed at a high level as a collection of mobile cells that include members that traffic throughout the body in search of invading pathogens as well as cells that reside as sentinels at portals of entry (i.e. the airways, skin, gastrointestinal tract, etc.).3 These cells belong to one of two major arms, the innate immune system and adaptive immune system. Innate immune cells such as neutrophils and macrophages are poised to rapidly respond to pathogen invasion, expressing receptors that recognize conserved molecular motifs characteristic of bacteria, viruses, and fungi, to quickly phagocytose (internalize) microbes and secrete reactive oxygen species or cytokines that provide an immediate response to invading pathogens. The adaptive immune system is comprised of T-cells and B-cells, including CD4+ helper T-cells that secrete cytokines to direct the functions of innate cells, killer cells, and B-cells; and CD8+ killer T-cells that recognize and destroy infected or transformed cells. B-cells play a canonical role in vaccine responses by producing antibodies that bind to and neutralize the ability of microbes to invade host cells and/or promote their phagocytosis. The adaptive immune system is so named because of the clonal nature of T and B lymphocytes– each T-cell and B-cell expresses a unique T-cell receptor or B-cell receptor, respectively, which is generated in part by a process of stochastic DNA recombination, enabling the pool of lymphocytes the potential to recognize any microbial antigen they may encounter.4 When a T- or B-cell binds an antigen (essentially, any biological molecule from a microbe that is recognized by a T-cell receptor (TCR) or B-cell receptor (BCR)), this triggers massive proliferation of the antigen-specific cell, generating a pool of effectors within ~7 days following exposure. These effector T-cells and B-cells play an important role in backing up innate immune defenses to clear the invading pathogen. Following pathogen clearance, the majority of these cells (~90%) undergo programmed cell death, leaving a small pool of differentiated memory cells that can remain for the lifetime of the individual, to provide rapid recall protection if the same microbe is ever encountered again.5 A final key group of immune cells are the antigen presenting cells (APCs), and particularly a critical APC known as the dendritic cell, which is responsible for activating naive T-cells (and in some cases B-cells).6,7 Dendritic cells (DCs) are innate-like cells that reside in all peripheral tissues, and which act as sentinels, collecting antigens from the surrounding fluid and staying on constant alert for “danger signals”- molecular motifs signifying tissue damage or pathogen invasion. DCs and other immune cells express a host of receptors that specifically recognize danger signals to trigger their activation; the most studied among these receptors are the Toll-like receptors.8 If activated by danger signals, DCs migrate from their home tissue through the lymphatic vessels to local draining lymph nodes, where they physically present antigen to T-cells and B-cells. For T-cell activation, this is through the loading of short (8–15 amino acids) peptide fragments of antigens into the cleft of major histocompatibility complex (MHC) molecules displayed on the DC surface. These peptides are surveyed by the TCRs of T-cells, and on finding a cognate peptide, T-cells become activated by the DC to proliferate and carry out their effector functions. The vastly complex set of cellular interactions summarized above (greatly oversimplified) is the network of interest to those interested in immune engineering, and in this review we aim to summarize the myriad ways in which materials scientists, chemical engineers, bioengineers, chemists, and physicists (often in collaboration with immunologists) are using nanomaterials as powerful tools to probe or manipulate immune responses for therapeutic ends. To set the stage for the rest of the review, we will briefly discuss two of the areas where synthetic nanoparticles have the prospect to play a significant role in the ongoing revolution of immunology in medicine– vaccines and active immunotherapy.

Progress in Nanomedicine: Approved and Investigational Nanodrugs.

Abstract: Nanomedicine is a relatively new and rapidly evolving field combining nanotechnology with the biomedical and pharmaceutical sciences.1-3 Nanoparticles (NPs) can impart many pharmacokinetic, efficacy, safety, and targeting benefits when they are included in drug formulations.1-5 Many nanodrugs have entered clinical practice, and even more are being investigated in clinical trials for a wide variety of indications.2 However, nanopharmaceuticals also face challenges, such as the need for better characterization, possible toxicity issues, a lack of specific regulatory guidelines, cost-benefit considerations, and waning enthusiasm among some health care professionals. 4,5 For these reasons, expectations regarding nanodrugs that are in early stages of development or clinical trials need to remain realistic.4.