Antigen administration via the gastrointestinal tract is used mostly in the study of allergy. It has distinctive effects, frequently eliciting a local antibody response in the intestinal lamina propria, while producing a systemic state of tolerance that manifests as a diminished response to the same antigen if subsequently administered in immunogenic form elsewhere in the body (see Chapter 12). This ‘split tolerance’ may be important in avoiding allergy to antigens in food, because the local response prevents food antigens from entering the body, while the inhibition of systemic immunity helps to prevent the formation of IgE antibodies, which are the cause of such allergies (see Chapter 14).
The immune response to an antigen is also influenced by the dose of immunogen administered. Below a certain threshold dose, most proteins do not elicit any immune response. Above the threshold dose, there is a gradual increase in the response as the dose of antigen is increased, until a broad plateau level is reached, followed by a decline at very high antigen doses (Fig. A.2). In general, secondary and subsequent immune responses occur at lower antigen doses and achieve higher plateau values, which is a sign of immunological memory.
Most proteins are poorly immunogenic or nonimmunogenic when administered by themselves. Strong adaptive immune responses to protein antigens almost always require that the antigen be injected in a mixture known as an adjuvant. An adjuvant is any substance that enhances the immunogenicity of substances mixed with it. Commonly used adjuvants are listed in Fig. A.3.
Adjuvants generally enhance immunogenicity in two different ways. First, adjuvants convert soluble protein antigens into particulate material, which is more readily ingested by phagocytic antigen-presenting cells such as macrophages and dendritic cells. For example, the antigen can be adsorbed on particles of the adjuvant (such as alum), be made particulate by emulsification in mineral oils, or be incorporated into the colloidal particles of immune stimulatory complexes (ISCOMs). Second, and more important, adjuvants contain PAMPs that elicit a strong innate immune response. When taken up by phagocytic cells, the PAMPs in the adjuvant stimulate inflammatory cytokine production and induce the activation of the antigen-presenting cell. The activated antigen-presenting cells upregulate abundant levels of co-stimulatory molecules that are important for activating T cells. Activated antigen-presenting cells also upregulate high levels of MHC class I and class II proteins, plus many of the proteins important for efficient antigen processing and presentation (see Section 3-12). Due to the strong local inflammatory responses induced by adjuvants that contain PAMPs, most of the adjuvants commonly used in experimental animals are not approved for use in humans.
The typical antigen dose–response curve shown here illustrates both the influence of dose on a primary antibody response (amounts of antibody produced expressed in arbitrary units) and the effect of the dose used for priming on a secondary antibody response elicited by a dose of antigen of 103 arbitrary mass units. Very low doses of antigen do not cause an immune response at all. Slightly higher doses seem to inhibit specific antibody production, an effect known as low-zone tolerance. Above these doses there is a steady increase in the response with antigen dose until an optimum response is reached; this response persists across a broad range of doses. Very high doses of antigen also inhibit immune responsiveness to a subsequent challenge, a phenomenon known as high-zone tolerance.