ISCOMs
Adjuvants, Immunologic
Diffusion Chambers, Culture
Nicotinic Acids
Acridines
Pharmacokinetics
Comparison of immunity generated by nucleic acid-, MF59-, and ISCOM-formulated human immunodeficiency virus type 1 vaccines in Rhesus macaques: evidence for viral clearance. (1/57)
The kinetics of T-helper immune responses generated in 16 mature outbred rhesus monkeys (Macaca mulatta) within a 10-month period by three different human immunodeficiency virus type 1 (HIV-1) vaccine strategies were compared. Immune responses to monomeric recombinant gp120SF2 (rgp120) when the protein was expressed in vivo by DNA immunization or when it was delivered as a subunit protein vaccine formulated either with the MF59 adjuvant or by incorporation into immune-stimulating complexes (ISCOMs) were compared. Virus-neutralizing antibodies (NA) against HIV-1SF2 reached similar titers in the two rgp120SF2 protein-immunized groups, but the responses showed different kinetics, while NA were delayed and their levels were low in the DNA-immunized animals. Antigen-specific gamma interferon (IFN-gamma) T-helper (type 1-like) responses were detected in the DNA-immunized group, but only after the fourth immunization, and the rgp120/MF59 group generated both IFN-gamma and interleukin-4 (IL-4) (type 2-like) responses that appeared after the third immunization. In contrast, rgp120/ISCOM-immunized animals rapidly developed marked IL-2, IFN-gamma (type 1-like), and IL-4 responses that peaked after the second immunization. To determine which type of immune responses correlated with protection from infection, all animals were challenged intravenously with 50 50% infective doses of a rhesus cell-propagated, in vivo-titrated stock of a chimeric simian immunodeficiency virus-HIVSF13 construct. Protection was observed in the two groups receiving the rgp120 subunit vaccines. Half of the animals in the ISCOM group were completely protected from infection. In other subunit vaccinees there was evidence by multiple assays that virus detected at 2 weeks postchallenge was effectively cleared. Early induction of potent type 1- as well as type 2-like T-helper responses induced the most-effective immunity. (+info)Immune-stimulating complexes induce an IL-12-dependent cascade of innate immune responses. (2/57)
The development of subunit vaccines requires the use of adjuvants that act by stimulating components of the innate immune response. Immune-stimulating complexes (ISCOMS) containing the saponin adjuvant Quil A are potential vaccine vectors that induce a wide range of Ag-specific responses in vivo encompassing both humoral and CD4 and CD8 cell-mediated immune responses. ISCOMS are active by both parenteral and mucosal routes, but the basis for their adjuvant properties is unknown. Here we have investigated the ability of ISCOMS to recruit and activate innate immune responses as measured in peritoneal exudate cells. The i.p. injection of ISCOMS induced intense local inflammation, with early recruitment of neutrophils and mast cells followed by macrophages, dendritic cells, and lymphocytes. Many of the recruited cells had phenotypic evidence of activation and secreted a number of inflammatory mediators, including nitric oxide, reactive oxygen intermediates, IL-1, IL-6, IL-12, and IFN-gamma. Of the factors that we investigated further only IL-12 appeared to be essential for the immunogenicity of ISCOMS, as IL-6- and inducible nitric oxide synthase knockout (KO) mice developed normal immune responses to OVA in ISCOMS, whereas these responses were markedly reduced in IL-12KO mice. The recruitment of peritoneal exudate cells following an injection of ISCOMS was impaired in IL-12KO mice, indicating a role for IL-12 in establishing the proinflammatory cascade. Thus, ISCOMS prime Ag-specific immune responses at least in part by activating IL-12-dependent aspects of the innate immune system. (+info)Augmentation of human influenza A virus-specific cytotoxic T lymphocyte memory by influenza vaccine and adjuvanted carriers (ISCOMS). (3/57)
There is a need to improve the ability of subunit vaccines to induce CD8(+) CTL responses in humans, especially for vaccines used to prevent illness by organisms that undergo antigenic variation at their major neutralizing antibody sites, e.g., influenza A viruses and human immunodeficiency virus. Murine models have demonstrated the protective role of cross-reactive CTL against influenza A virus antigenic drift. We tested the ability of an adjuvanted carrier (Iscomatrix) to help human antigen-presenting cells present formalin-killed influenza vaccine to human CD8(+) CTL clones in vitro and in vaccinated humans. The results of a randomized, double-blind, controlled clinical study demonstrate that a single dose of a vaccine formulated into Iscom particles increased influenza A virus-specific CTL memory in 50-60% of recipients, compared to 5% of the recipients of the standard influenza vaccine. (+info)Use of herpes simplex virus (HSV) type 1 ISCOMS 703 vaccine for prophylactic and therapeutic treatment of primary and recurrent HSV-2 infection in guinea pigs. (4/57)
The effect of subunit vaccination on the incidence and severity of primary and recurrent genital herpes was investigated in the female guinea pig model of herpes simplex virus (HSV) type 2 genital infection. After prophylactic immunization with zwitterionic detergent-solubilized HSV-1 glycoproteins formulated with alhydrogel or as immunostimulating complex particles, significant reductions in the incidence and severity of primary herpetic illness were observed in both vaccinated groups compared with immunization-naive controls. There was a significant reduction in the incidence of spontaneous herpetic recurrences after administration of HSV-1 antigens formulated as immunostimulatory complexes to guinea pigs in a prophylactic mode (P<.01). Increased levels of both postimmunization and postchallenge ELISA and neutralizing antibodies were significant correlates of protection against primary herpetic disease in a prophylactic scenario. However, no correlation was observed between elevated ELISA or neutralizing antibody levels and protection against recurrent disease following prophylactic or therapeutic administration of HSV-1 subunit vaccines. (+info)Priming with Chlamydia trachomatis major outer membrane protein (MOMP) DNA followed by MOMP ISCOM boosting enhances protection and is associated with increased immunoglobulin A and Th1 cellular immune responses. (5/57)
We previously reported that DNA vaccination was able to elicit cellular immune responses and partial protection against Chlamydia trachomatis infection. However, DNA immunization alone did not generate immune responses or protection as great as that induced by using live organisms. In this study, we evaluated the immunologic effects of a combinational vaccination approach using C. trachomatis mouse pneumonitis (MoPn) major outer membrane protein (MOMP) DNA priming followed by boosting with immune-stimulating complexes (ISCOM) of MOMP protein (MOMP ISCOM) for protection of BALB/c mice against MoPn lung infection. Substantially better protection to challenge infection was observed in mice given combinational vaccination compared with mice given MOMP ISCOM immunization alone, and the protection approximated that induced by live organisms. Enhanced protection was correlated with stronger delayed-type hypersensitivity, higher levels of gamma interferon production, and increased immunoglobulin A antibody responses in lung homogenates. The results indicate that DNA priming followed by ISCOM protein boosting may be useful in designing a fully protective chlamydial vaccine. (+info)Induction of protective immunity against Chlamydia trachomatis genital infection by a vaccine based on major outer membrane protein-lipophilic immune response-stimulating complexes. (6/57)
The significance of delivery systems in modern vaccine design strategies is underscored by the fact that a promising vaccine formulation may fail in vivo due to an inappropriate delivery method. We evaluated the immunogenicity and efficacy of a candidate vaccine comprising the major outer membrane protein (MOMP) of Chlamydia trachomatis delivered with the lipophilic immune response-stimulating complexes (ISCOMs) as a vehicle with adjuvant properties, in a murine model of chlamydial genital infection. Immunocompetent BALB/c mice were immunized intranasally (IN) or intramuscularly (IM) with MOMP, MOMP-ISCOMs, and live or heat-inactivated C. trachomatis serovar D. The level of local genital mucosal Th1 response was measured by assaying for antigen-specific Th1 cell induction and recruitment into the genital mucosa at different times after immunization. Immunization with MOMP-ISCOMs by the IM route induced the greatest and fastest local genital mucosal Th1 response, first detectable 2 weeks after exposure. Among the other routes and regimens tested, only IN immunization with MOMP-ISCOMs induced detectable and statistically significant levels of local genital mucosal Th1 response during the 8-week test period (P < 0.001). In addition, when T cells from immunized mice were adoptively transferred into syngeneic naive animals and challenged intravaginally with Chlamydia, recipients of IM immunization of MOMP-ISCOMs cleared their infection within 1 week and were resistant to reinfection. Animals that received IN immunization of MOMP-ISCOMs were partially protected, shedding fewer chlamydiae than did control mice. Altogether, the results suggested that IM delivery of MOMP-ISCOMs may be a suitable vaccine regimen potentially capable of inducing protective mucosal immunity against C. trachomatis infection. (+info)Characterization of hepatitis C virus core-specific immune responses primed in rhesus macaques by a nonclassical ISCOM vaccine. (7/57)
Current therapies for the treatment of hepatitis C virus (HCV) infection are only effective in a restricted number of patients. Cellular immune responses, particularly those mediated by CD8(+) CTLs, are thought to play a role in the control of infection and the response to antiviral therapies. Because the Core protein is the most conserved HCV protein among genotypes, we evaluated the ability of a Core prototype vaccine to prime cellular immune responses in rhesus macaques. Since there are serious concerns about using a genetic vaccine encoding for Core, this vaccine was a nonclassical ISCOM formulation in which the Core protein was adsorbed onto (not entrapped within) the ISCOMATRIX, resulting in approximately 1-microm particulates (as opposed to 40 nm for classical ISCOM formulations). We report that this Core-ISCOM prototype vaccine primed strong CD4(+) and CD8(+) T cell responses. Using intracellular staining for cytokines, we show that in immunized animals 0.30-0.71 and 0.32-2.21% of the circulating CD8(+) and CD4(+) T cells, respectively, were specific for naturally processed HCV Core peptides. Furthermore, this vaccine elicited a Th0-type response and induced a high titer of Abs against Core and long-lived cellular immune responses. Finally, we provide evidence that Core-ISCOM could serve as an adjuvant for the HCV envelope protein E1E2. Thus, these data provide evidence that Core-ISCOM is effective at inducing cellular and humoral immune responses in nonhuman primates. (+info)CTA1-DD-immune stimulating complexes: a novel, rationally designed combined mucosal vaccine adjuvant effective with nanogram doses of antigen. (8/57)
Mucosally active vaccine adjuvants that will prime a full range of local and systemic immune responses against defined antigenic epitopes are much needed. Cholera toxin and lipophilic immune stimulating complexes (ISCOMS) containing Quil A can both act as adjuvants for orally administered Ags, possibly by targeting different APCs. Recently, we have been successful in separating the adjuvant and toxic effects of cholera toxin by constructing a gene fusion protein, CTA1-DD, that combines the enzymatically active CTA1-subunit with a B cell-targeting moiety, D, derived from Staphylococcus aureus protein A. Here we have extended this work by combining CTA1-DD with ISCOMS, which normally target dendritic cells and/or macrophages. ISCOMS containing a fusion protein comprising the OVA(323-339) peptide epitope linked to CTA1-DD were highly immunogenic when given in nanogram doses by the s.c., oral, or nasal routes, inducing a wide range of T cell-dependent immune responses. In contrast, ISCOMS containing the enzymatically inactive CTA1-R7K-DD mutant protein were much less effective, indicating that at least part of the activity of the combined vector requires the ADP-ribosylating property of CTA1. No toxicity was observed by any route. To our knowledge, this is the first report on the successful combination of two mechanistically different principles of adjuvant action. We conclude that rationally designed vectors consisting of CTA1-DD and ISCOMS may provide a novel strategy for the generation of potent and safe mucosal vaccines. (+info)ISCOMs, or Immune Stimulating Complexes, are non-inflammatory, virus-like particles that are used as a delivery system for vaccines. They were developed to improve the immune response to antigens, which are substances that trigger an immune response. ISCOMs are made up of saponins, cholesterol, phospholipids, and antigen. The saponins in ISCOMs are derived from the bark of the Quillaia saponaria tree and have adjuvant properties, which means they help to boost the immune response to the antigen.
The unique structure of ISCOMs allows them to be taken up by both immune cells that reside in the skin and mucous membranes (known as antigen-presenting cells) and by cells that line the inside of blood vessels (known as endothelial cells). This broad cellular uptake helps to stimulate both the humoral and cell-mediated arms of the immune system, leading to a strong and balanced immune response.
ISCOMs have been studied as a delivery system for a variety of vaccines, including those against infectious diseases such as HIV, influenza, and tuberculosis. They have also been explored as a potential platform for cancer vaccines.
Immunologic adjuvants are substances that are added to a vaccine to enhance the body's immune response to the antigens contained in the vaccine. They work by stimulating the immune system and promoting the production of antibodies and activating immune cells, such as T-cells and macrophages, which help to provide a stronger and more sustained immune response to the vaccine.
Immunologic adjuvants can be derived from various sources, including bacteria, viruses, and chemicals. Some common examples include aluminum salts (alum), oil-in-water emulsions (such as MF59), and bacterial components (such as lipopolysaccharide or LPS).
The use of immunologic adjuvants in vaccines can help to improve the efficacy of the vaccine, particularly for vaccines that contain weak or poorly immunogenic antigens. They can also help to reduce the amount of antigen needed in a vaccine, which can be beneficial for vaccines that are difficult or expensive to produce.
It's important to note that while adjuvants can enhance the immune response to a vaccine, they can also increase the risk of adverse reactions, such as inflammation and pain at the injection site. Therefore, the use of immunologic adjuvants must be carefully balanced against their potential benefits and risks.
Diffusion chambers are devices used in tissue culture and microbiology to maintain a sterile environment while allowing for the exchange of nutrients, gases, or other molecules between two separate environments. In the context of cell or tissue culture, diffusion chambers are often used to maintain cells or tissues in a controlled environment while allowing them to interact with other cells, molecules, or drugs present in a separate compartment.
Culture diffusion chambers typically consist of two compartments separated by a semi-permeable membrane that allows for the passive diffusion of small molecules. One compartment contains the cells or tissues of interest, while the other compartment may contain various nutrients, growth factors, drugs, or other substances to be tested.
The use of diffusion chambers in cell and tissue culture has several advantages, including:
1. Maintaining a sterile environment for the cells or tissues being cultured.
2. Allowing for the exchange of nutrients, gases, or other molecules between the two compartments.
3. Enabling the study of cell-cell interactions and the effects of various substances on cell behavior without direct contact between the cells and the test substance.
4. Providing a means to culture sensitive or difficult-to-grow cells in a controlled environment.
Diffusion chambers are widely used in research settings, particularly in the fields of cell biology, tissue engineering, and drug development.
Niacin, also known as nicotinic acid, is a form of vitamin B3 (B-complex vitamin) that is used by the body to turn food into energy. It is found in various foods including meat, fish, milk, eggs, green vegetables, and cereal grains. Niacin is also available as a dietary supplement and prescription medication.
As a medication, niacin is primarily used to treat high cholesterol levels. It works by reducing the production of LDL (bad) cholesterol in the body and increasing the levels of HDL (good) cholesterol. Niacin can also help lower triglycerides, another type of fat found in the blood.
Niacin is available in immediate-release, sustained-release, and extended-release forms. The immediate-release form can cause flushing of the skin, itching, tingling, and headaches, which can be uncomfortable but are not usually serious. The sustained-release and extended-release forms may have fewer side effects, but they can also increase the risk of liver damage and other serious side effects.
It is important to note that niacin should only be taken under the supervision of a healthcare provider, as it can interact with other medications and have potentially serious side effects.
Skin absorption, also known as percutaneous absorption, refers to the process by which substances are taken up by the skin and pass into the systemic circulation. This occurs when a substance is applied topically to the skin and penetrates through the various layers of the epidermis and dermis until it reaches the capillaries, where it can be transported to other parts of the body.
The rate and extent of skin absorption depend on several factors, including the physicochemical properties of the substance (such as its molecular weight, lipophilicity, and charge), the concentration and formulation of the product, the site of application, and the integrity and condition of the skin.
Skin absorption is an important route of exposure for many chemicals, drugs, and cosmetic ingredients, and it can have both therapeutic and toxicological consequences. Therefore, understanding the mechanisms and factors that influence skin absorption is crucial for assessing the safety and efficacy of topical products and for developing strategies to enhance or reduce their absorption as needed.
Acridines are a class of heterocyclic aromatic organic compounds that contain a nucleus of three fused benzene rings and a nitrogen atom. They have a wide range of applications, including in the development of chemotherapeutic agents for the treatment of cancer and antibacterial, antifungal, and antiparasitic drugs. Some acridines also exhibit fluorescent properties and are used in research and diagnostic applications.
In medicine, some acridine derivatives have been found to intercalate with DNA, disrupting its structure and function, which can lead to the death of cancer cells. For example, the acridine derivative proflavin has been used as an antiseptic and in the treatment of certain types of cancer. However, many acridines also have toxic side effects, limiting their clinical use.
It is important to note that while acridines have potential therapeutic uses, they should only be used under the supervision of a qualified healthcare professional, as they can cause harm if not used properly.
Pharmacokinetics is the branch of pharmacology that deals with the movement of a drug in the body after administration. It involves the processes of absorption, distribution, metabolism, and excretion (ADME) of drugs.
1. Absorption: This is the process by which a drug is taken into the body and made available for distribution to the site of action.
2. Distribution: This refers to the dispersion of the drug throughout the body after absorption. It involves the transfer of the drug from the bloodstream into various tissues and organs.
3. Metabolism: This is the biotransformation of a drug by enzymes, usually in the liver, into metabolic products (also known as metabolites). These metabolites may be pharmacologically active, inactive, or toxic.
4. Excretion: This is the process by which drugs and their metabolites are eliminated from the body, typically through the kidneys (urine), lungs (exhaled air), skin (sweat), or gastrointestinal tract (feces).
Understanding pharmacokinetics is crucial for determining the optimal dosage regimen of a drug to achieve and maintain its therapeutic concentration in the body while minimizing potential side effects.