An adjuvant is any agent or substance that enhances an immune response. In most cases, adjuvants do not elicit immunity to themselves, but they can and do influence every aspect of the response to the antigen they accompany: the amount of antibody made, its specificity, which epitopes of a given protein are responded to, the isotype of the response, its avidity, duration, memory, and so on. In a very real sense, they are vital to vaccine development.

General Mechanisms of Adjuvant Action. Most adjuvants induce a protective or neutralizing antibody response, and over the years this has been the focus of most adjuvant research. Fewer adjuvants have been looked at for delayedtype hypersensitivity (DTH) or cellular immune response. And only recently have researchers begun to look at the small number of adjuvants that can induce Class I-restricted CTL responses. This research, going back to 1979, has identified a number of general mechanisms by which adjuvants work. One is the so-called “depot effect” —the antigen persists longer because it has been incorporated in an emulsion and is released slowly over time (e.g., Freund’s adjuvant). Another is the selective antigen localization in thymic-dependent areas.

However, the crucial mechanism is probably macrophage activation and the generation of inflammation. Indeed, this is how adjuvants were first discovered early in this century—horses that developed a sterile abscess at the injection site had much higher titers of antibody, so researchers started creating abscesses and injecting antigen into the abscess to boost the response. Freund’s adjuvant certainly induces inflammation, which is why it is not used in humans.

Other proposed mechanisms for adjuvant activity include increased uptake and presentation by antibody-presenting cells; processing pathway switching; specific or nonspecific stimulation of various helper T-cells; stimulation of increased cytokine production; B-cell isotype switching; and maturation of precursor cells. The specifics for any given adjuvant can be difficult to work out, because these are fairly complex substances that do several different things at once. In the past few decades, much activity has focussed on refining adjuvants down to a simpler, less toxic substance that can be used with greater safety.

On the molecular level, adjuvants appear to enhance the production of costimulatory cytokines. These include IL-1-beta, IL-6, and tumor necrosis factor (TNF), which are crucial for the initiation of immune response. This in turn upregulates costimulatory molecules such as B7, CD8–28, and various other adhesion molecules on T-cells and B-cells. In the future, it may be possible to formulate new adjuvants that selectively exploit these mechanisms. For example, a recent article indicates that the CTLA-4 ligand on T-cells gives a very inhibitory signal to the T-cell; inhibition of that pathway would probably have very good adjuvant effects.