Immunologic adjuvant

From Wikipedia, the free encyclopedia In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself.[1] The word ³adjuvant´ comes from the Latin word adiuvare, meaning to help or aid.[2] "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."[3] Adjuvants have been whimsically called the dirty little secret of vaccines[4] in the scientific community. This dates from the early days of commercial vaccine manufacture, when significant variations in the effectiveness of different batches of the same vaccine were observed, correctly assumed to be due to contamination of the reaction vessels. However, it was soon found that more scrupulous attention to cleanliness actually seemed to reduce the effectiveness of the vaccines, and that the contaminants ± "dirt" ± actually enhanced the immune response. There are many known adjuvants in widespread use, including oils, aluminium salts, and virosomes, although precisely how they work is still not entirely understood.

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1 Overview o 1.1 Inorganic adjuvants  1.1.1 Aluminium salts o 1.2 Organic adjuvants  1.2.1 Oil-based o 1.3 Virosomes o 1.4 Experimental adjuvants 2 Adjuvants and the adaptive immune response 3 Adjuvants and toll-like receptors 4 Medical complications o 4.1 Humans o 4.2 Animals 5 Controversy 6 See also 7 External links 8 References

[edit] Overview

[edit] Oil-based Oil-based adjuvants are commonly used in some veterinary vaccines. and serve to amplify fusogenic activity and therefore facilitate the uptake into antigen presenting cells (APC) and induce a natural antigen-processing pathway.[11] [edit] Experimental adjuvants .[10] These salts are unfavorable.[5] Because immune systems have evolved to recognize these specific antigenic moieties. and thus providing increased immunity to a particular disease. which include liposomes. and endocytosed nucleic acids such as double-stranded RNA (dsRNA).[7][8] Two common salts include aluminium phosphate and aluminium hydroxide.[9] During the last two decades. molecular cages for antigen. the adjuvant capabilities of virosomes are independent of any inflammatory reaction. The delivery of the antigen by virosomes to the immune system in a way that mimics a natural path may be a reason why virosome-based vaccines stand out due to their excellent safety profile. single-stranded DNA (ssDNA). However. lipopolysaccharide (LPS).[6] Furthermore. and macrophages by mimicking a natural infection. organic adjuvants are more commonly used in animal vaccines.Adjuvants in immunology are often used to modify or augment the effects of a vaccine by stimulating the immune system to respond to the vaccine more vigorously. since they develop their effect by inducing local inflammation. and unmethylated CpG dinucleotide-containing DNA. that also carry the potential to augment immunogenicity. so called PAMPs. some of which are inorganic (such as alum). because adjuvants are attenuated beyond any function of virulence. [edit] Virosomes Another market-approved adjuvant and carrier system are virosomes. a variety of technologies have been investigated to improve the widely-used adjuvants based on aluminium salts. the organic compound Squalene is also used. Virosomes contain a membrane-bound hemagglutinin and neuraminidase derived from the influenza virus. the presence of an adjuvant in conjunction with the vaccine can greatly increase the innate immune response to the antigen by augmenting the activities of dendritic cells (DCs). In contrast. These are the most common adjuvants in human vaccines. Adjuvants accomplish this task by mimicking specific sets of evolutionarily conserved molecules. which is also the basis for the extended side-effect pattern of this adjuvant.[citation needed] [edit] Inorganic adjuvants [edit] Aluminium salts There are many adjuvants. they pose little or no independent threat to a host organism. [edit] Organic adjuvants While Aluminium salts are popularly used in human vaccines. components of bacterial cell walls. lymphocytes.

In order to understand the links between the innate immune response and the adaptive immune response to help substantiate an adjuvant function in enhancing adaptive immune responses to the specific antigen of a vaccine.[12] The compound QS21 is under investigation as a possible immunological adjuvant[13] as is Novartis' (formerly Chiron) MF59. a recent study has observed that adjuvants may exert their immune-enhancing effects according to five immune-functional activities. DCs then migrate to the lymph nodes where T cells (adaptive immune cells) wait for signals to trigger their activation. T cells can then recognize these clippings and undergo a cellular transformation resulting in their own activation. mast cells also release chemokines which result in the positive chemotaxis of other immune cells of both the innate and adaptive immune responses to the infected area. Specifically.[19] . When the amount of communication that takes place between the innate immune response and the adaptive immune response with the onset of infection is considered it becomes difficult to separate the two systems.[15] In the lymph nodes.[14] [edit] Adjuvants and the adaptive immune response One misconception concerning adjuvant function is that an adjuvant-enhanced innate immune response should affect only the transient reaction of the innate immune response and not the more long-lived effects of the adaptive immune response. This process carried out by both DCs and macrophages is termed antigen presentation and represents a physical link between the innate and adaptive immune responses. the following points should be considered: y y y y y y Innate immune response cells such as Dendritic Cells (DCs) engulf pathogens through a process called phagocytosis. Upon activation.An increasing number of vaccines with squalene and phosphate adjuvants are being tested on humans. an adjuvant-enhanced innate immune response results in an enhanced adaptive immune response.[17][18] Due to the variety of mechanisms and links between the innate and adaptive immune response. it is however important to realize the interconnected nature of the two systems. Macrophages can also activate T cells in a similar approach (but do not do so naturally).[16] T cells possess characteristics of both the innate and adaptive immune responses. mast cells release heparin and histamine to effectively increase trafficking to and seal off the site of infection to allow immune cells of both systems to clear the area of pathogens. In addition. DCs mince the engulfed pathogen and then express the pathogen clippings as antigen on their cell surface by coupling them to a special receptor known as a major histocompatibility complex (MHC).[citation needed] Although it may appear fitting to separate the two systems.

adjuvants are believed to increase the innate immune response to antigen by interacting with pattern recognition receptors (PRRs). TLRs were first discovered in drosophila.[20][21] In fact. This means that the organism will be exposed to the antigen for a longer duration. it was found that adjuvants all help in the translocation of antigens to the lymph nodes where they can be recognized by T cells.either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection . and are membrane bound pattern recognition receptors (PRRs) responsible for detecting most (although certainly not all) antigen-mediated infections.y y y y y First. Prevailing TLR ligands described to date (all of which elicit adjuvant effects) include many evolutionarily conserved molecules such as LPS. To date. including protein kinases (IKKi. four adapter proteins have been wellcharacterized. IRAK4. This will ultimately lead to greater T cell activity resulting in a heightened clearance of pathogen throughout the organism.[29][30] The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. due to the presence of special Immune receptors called TLRs that are expressed on leukocyte membranes.[31][32][33][34] These recruited proteins are then responsible for the subsequent activation of other downstream proteins. flagellin. adjuvants provide physical protection to antigens which grants the antigen a prolonged delivery. Tram and Tirap (also called Mal). lipoproteins. lipopeptides. [edit] Adjuvants and toll-like receptors The ability of immune system to recognize molecules that are broadly shared by pathogens is. inducing greater release of danger signals by chemokine releasing cells such as helper T cells and mast cells. These proteins are known as MyD88. IRAK1.[23][24][25][26][27][28] The binding of ligand . each with its own characteristic ligand. some studies have shown that in the absence of TLR. adjuvants help to increase the capacity to cause local reactions at the injection site (during vaccination). unmethylated CpG islands and various other forms of DNA and RNA classically released by bacteria and viruses. they induce the release of inflammatory cytokines which helps to not only recruit B and T cells at sites of infection but also to increase transcriptional events leading to a net increase of immune cells as a whole. Third. on accessory cells. Second.to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.[22] There are at least thirteen different forms of TLR. in part. leukocytes become unresponsive (no inflammatory responses) to some microbial components such as LPS. and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that . specifically Toll-like receptors (TLRs). making the immune system more robust as it makes use of the additional time by upregulating the production of B and T cells needed for greater immunological memory in the adaptive immune response. Fourth. Finally. It is believed that upon activation. Trif. double-stranded RNA. TLRs recruit adapter proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell in order to propagation the antigen-induced signal transduction pathway.

natural killer cells). fibroblasts).[36] [edit] Animals Aluminum adjuvants have caused motor neuron death in mice[37] and oil-water suspensions have been reported to increase the risk of autoimmune disease in mice.orchestrate inflammatory responses and other transcriptional events. . Finally. macrophages.[39] In cats. Some of these events lead to cytokine production. vaccinations have been linked to sarcomas.[35] This further substantiates the importance of administering vaccines with adjuvants in the form of TLR ligands as they will be capable of eliciting their positive effects across the entire spectrum of innate and adaptive immunity. [edit] Medical complications [edit] Humans Aluminium salts used in many human vaccines are generally regarded as safe. proliferation. In short. while others lead to greater adaptive immunity. all TLR ligands are adjuvants but not all adjuvants are TLR ligands. Nevertheless.[30] The high sensitivity of TLR for microbial ligands is what makes adjuvants that mimic TLR ligands such a prime candidate for enhancing the overall effects of antigen specific vaccinations on immunological memory.[38] Squalene has caused rheumatoid arthritis in rats already prone to arthritis. there are certainly adjuvants whose immunestimulatory function completely bypasses the putative requisite for TLR signaling. the expression of TLRs is vast as they are found on the cell membranes of innate immune cells (DCs. cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells. and survival.