IMMUNOLOGY - Roit I. - Mir 2000

Chapter 13. Regulation of the Immune Response

■ The Immune Response is regulated by diverse mechanisms that ensure the restoration of The Immune System's baseline state once the reaction to a given antigen is no longer required.

■ The ultimate outcome of any immune response depends on multiple factors, including The properties of the antigen, its dose and route of administration, as well as the genetic Background of the host.

■ IMMUNOGLOBULINS can play a positive role in the immune response by acting as anti-idiotypic Antibodies or by forming immune complexes. Conversely, Igs may play a negative role by dampening the antigenic stimulus—either by masking antigen determinants through binding or by facilitating the clearance of the antigen from the body.

■ The immune response can depend on the ability of antigen-presenting Cells to provide costimulation to T lymphocytes.

■ T cells are capable of regulating the immune response. Adoptive transfer experiments have demonstrated that CD4⁺ T lymphocytes can downregulate subsequent immune responses. CD8⁺ T cells also exert regulatory effects. Furthermore, cytokine production by T lymphocytes influences the type of immune response elicited by an antigen.

■ Genetically, the immune response depends on both MHC and non-MHC genes. In addition, since it is influenced by the neuroendocrine system, it also relies on genetic factors that govern the Functions of this system.

Like all biological functions, the immune response is governed by a variety of regulatory mechanisms. These mechanisms ensure the restoration of the initial, "resting" state of the immune system when an Immune Response to a specific antigen is no longer needed. An effective immune response results from the interaction between an antigen and an entire network of immunocompetent cells. The Nature of the immune response, both quantitatively and qualitatively, depends on numerous factors, including the type of antigen, its dose and route of administration, the properties of antigen-presenting cells (APCs), the genetic background of the Organism, and previous contact of the immune system with the same or a cross-reacting antigen. Specific antibodies can also influence the immune response. Some of these regulatory factors are examined in detail in other chapters (see Chapters 10 and 11) and are only briefly discussed here.

THE ANTIGEN AS A FACTOR IN IMMUNOREGULATION

Activation of T AND B cells occurs As a result of the effective binding of antigenic material by their antigen-specific receptors. T-Cell receptors interact not with the native antigen, but rather with peptide fragments generated by its Processing and presented in association with Class I or class II MHC molecules (see Chapter 9). The outcome of the immune response is significantly influenced by the Nature of the antigen, its dose, and the route of administration.

The type of immune response depends on the nature of the antigen

Different Antigens induce distinct TYPES OF IMMUNE responses. Bacterial capsular polysaccharide antigens typically elicit solely a humoral response (IgM production), whereas protein antigens elicit both cellular and humoral responses. Microorganisms localized intracellularly within the host, particularly certain Bacteria, parasites, and Viruses, induce a cell-mediated immune response, whereas soluble protein antigens provoke a humoral response. Cell-mediated immune responses can also be triggered by antigens such as silicon-containing compounds.

An effective immune response ensures the elimination of the antigen from the body. Following this, lymphocytes return to a resting state (continuous contact with the antigen is required to maintain T- and B-cell proliferation). However, certain antigens (such as components of intracellular microorganisms) may not be cleared from the body as efficiently, leading to a prolonged immune response with pathological consequences for the host (see Chapter 26).

High doses of antigen can induce tolerance

Administration of a very high dose of antigen frequently induces specific T-cell tolerance, and occasionally B-cell tolerance as well. This phenomenon is commonly observed when antigens are injected into newborn mice. For a long time, this was attributed to the immaturity of the immune system. However, it has now been established that newborn mice are capable of developing fully competent immune responses (Fig. 13.1); the lack of an immune response in certain cases is related not to T-cell immaturity, but to a phenomenon known as immune deviation, in which The production of non-protective type II cytokines dominates over protective type I cytokines. Moreover, T-independent polysaccharide antigens have been shown to induce B-cell tolerance when administered in large doses. The phenomenon of immunological tolerance and its mechanisms are discussed in Chapter 14.

Fig. 13.1. Newborn mice were infected with the virus at doses of 0.3 or 1000 plaque-forming units (PFU), and The Effect of cytotoxic T lymphocytes (Tc) on virus-infected target cells was studied. Simultaneously, the production of IFNγ (a Th1 cytokine) and IL-4 (a Th2 cytokine) in response to viral infection was determined. Mice infected with the low dose of virus exhibited a Th1 response and protection against infection. Results are expressed in relative units.

Depending on the route of administration, an immune response may either occur or fail to develop

The route of antigen administration has been shown to be of critical importance for the generation of an immune response. Antigens administered subcutaneously or intradermally elicit an immune response, whereas intravenous injection, oral ingestion, or aerosol delivery may induce tolerance or immune deviation. (In the latter case, instead of a response mediated by one subset of CD4⁺ T cells, a reaction mediated by a different subset of CD4⁺ T lymphocytes ensues.) For instance, rodents fed Ovalbumin (OA) or myelin basic protein (MBP) fail to respond to subsequent challenge with the corresponding antigen. Furthermore, administration of MBP protects animals against The Development of an autoimmune disease—experimental allergic encephalomyelitis (EAE). This phenomenon can be exploited for therapeutic purposes in allergic disorders; recent studies have demonstrated that oral administration of a T-cell epitope from the house dust mite allergen Der p 1 can induce tolerance to the native antigen. The underlying mechanism(s) of tolerance may involve either anergy or immune deviation.

Similar observations have been made when antigens are administered as aerosols. Experiments in mice have demonstrated that intranasal delivery of an encephalitogenic peptide as an aerosol suppresses the development of EAE induced by subsequent conventional (subcutaneous) administration of the peptide (Fig. 13.2). This finding may also be relevant to the development of therapeutic strategies, since aerosol delivery can inhibit not only the specific antigen administered in this manner but also other antigens capable of inducing EAE.

Fig. 13.2. Mice were administered a single intranasal dose of 100 µg of peptide (residues 1–11 of myelin basic protein) or vehicle as an aerosol, followed 7 days later by the same peptide in adjuvant administered subcutaneously. Mice pretreated with the peptide showed significantly reduced severity of EAE disease.

A clear illustration of how the route of antigen administration can influence the immune response is provided by studies of lymphocytic choriomeningitis virus (LCMV) infection in mice. Mice primed with a peptide in incomplete Freund's adjuvant via subcutaneous injection develop Immunity to LCMV. However, if the same peptide is administered intraperitoneally, the animals become tolerant and lose The ability to clear the virus (Fig. 13.3).

Fig. 13.3. Mice were primed with LCMV or administered 100 μg of the LCMV peptide. The peptide was injected in incomplete Freund's adjuvant either subcutaneously (s.c.) or three times intraperitoneally (i.p.). Afterward, the mice were infected with LCMV (day 0). On day 4, the virus titer in the animals' Spleen was determined. In mice pre-administered with the peptide or LCMV subcutaneously, neutralizing antibodies were synthesized and a protective immune response against the virus developed; in animals that received the peptide intraperitoneally, immunity did not occur. On day 10, the cytotoxic activity of T cells was determined. LCMV peptide-specific Tc activity was detected in the control group (no pretreatment); in the group with intraperitoneal peptide pretreatment, this activity was practically absent.