IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 14. Immunological Tolerance

TOLERANCE INDUCED ARTIFICIALLY IN VIVO

Tolerance in vivo can be induced through various approaches

Chimerism associated with tolerance. Tolerance can be induced in non-immunocompetent recipients—such as newborn animals or adult subjects subjected to immunosuppressive Treatment (via total body irradiation, drug administration such as cyclosporin, or antilymphocyte Antibodies like antilymphocyte globulin, anti-CD4 antibodies, etc.)—by administering allogeneic Cells. Maintaining such tolerance requires sustaining a certain level of chimerism (i.e., the coexistence of genetically distinct donor and recipient cells). The most effective way to achieve this is by transplanting cells capable of self-renewal, such as Bone Marrow cells.

If mature T cells are present in the allogeneic inoculum, they may mount an Immune Response against the recipient's Histocompatibility Antigens, triggering a severe and frequently fatal condition known as graft-versus-host disease.

Antibodies to B-Cell coreceptors induce transplant tolerance. Tolerance to transplanted Tissues can be induced using Monoclonal Antibodies directed against T-cell CD4 and CD8 molecules (these antibodies may be of two types: depleting or non-depleting T cells). In this Setting, tolerance to an allogeneic Skin graft can be achieved in the absence of cellular chimerism.

Soluble antigens induce tolerance. Tolerance can be induced in both newborn and adult animals by administering soluble protein antigens in a disaggregated form. T AND B cells differ in their susceptibility to the tolerogenic action of such antigens. For instance, tolerance in splenic and thymic T cells develops within hours of administering very low doses of antigen. B-cell tolerance in the Spleen requires significantly higher antigen doses and develops much more slowly (Fig. 14.14). The antigen concentration required to induce B-cell tolerance in newborns is approximately one-hundredth of that required in adults.

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Fig. 14.14. Mice were injected with a T-dependent antigen (human globulin) in tolerogenic doses, and the duration of tolerance was evaluated. T-cell tolerance developed faster and lasted longer than B-cell tolerance. The state of tolerance in bone marrow B cells emerged later than in splenic B lymphocytes. Typically, tolerogenic doses for T cells were significantly lower than those for B cells—10 µg versus 1–10 mg, respectively—representing a 1000-fold difference.

Oral administration of antigens induces immunological tolerance. The mechanisms underlying tolerance induced by this route can vary. High doses of antigens may induce anergy or deletion; here, anergy refers to a state of cellular unresponsiveness preceding cell death (see above). At lower doses, orally administered antigen may prime mucosal T cells. Because an effective antibody response in the gut requires immunoglobulin class switching to IgA production, it is unsurprising that oral antigen administration induces T cells that support The formation of IgA antibodies. These Th2-like cells secrete cytokines, including IL-10 and TGFβ (transforming growth factor β), and suppress inflammatory responses mediated by Th1 lymphocytes. TGFβ inhibits the proliferation and Functions of B cells, cytotoxic T cells, and NK cells, suppresses cytokine production by lymphocytes, and counteracts the effects of TNF. Although the induction of Th2 cells in the mucosal membrane is an antigen-specific process, the suppressive action of cytokines such as TGFβ is non-specific. Consequently, inducing so-called oral tolerance to one antigen can suppress the Immune Response to a second, co-administered antigen. This "bystander suppression" effect exerted by mucosal Th2 lymphocytes allows for the therapeutic modulation of complex organ-specific autoimmune diseases through the oral administration of an antigen derived from the target tissue.

Mucosal surfaces of other Organs have been shown to be equally effective in eliciting antigen-specific tolerance. Intranasal administration of MHC class II-restricted Peptides has been utilized to modulate both humoral and cellular immune responses. Furthermore, appropriate antigens inhaled into the Lungs as aerosols can be employed to suppress allergic reactions to foreign antigens or autoimmune responses to self-antigens. Because this method successfully suppresses both autoimmune and allergic reactions mediated by Th1 and Th2 cells, respectively, the underlying mechanism of tolerance in this case does not appear to involve immune deviation. Other cell types, including CD8⁺ cells, may be responsible for suppressing the immune response following the aerosol delivery of protein antigens.

Targeted antigen delivery to naive B cells induces immune deviation. Immune deviation can be elicited by targeting unprimed B cells with an antigen coupled to monoclonal antibodies against IgD (an immunoglobulin expressed on the B-cell surface). In this approach, the peptide antigen is presented by B cells, shifting the immune response toward a Th2-type profile. This strategy can be applied to modulate inflammatory responses to peptide antigens in experimentally induced autoimmune conditions, such as experimental autoimmune encephalomyelitis (EAE).

Intense clonal proliferation can lead to clonal exhaustion and tolerance. Tolerance in T lymphocytes (and to a lesser extent, B cells) can result from clonal exhaustion, which occurs at the end-stage of a robust immune response. Repeated antigen administration can drive the differentiation of all antigen-reactive cells into short-lived effector cells, leaving the Organism devoid of cells capable of responding to subsequent antigen exposure.

Anti-idiotypic responses may be linked to tolerance. The binding site of an antibody can act as an antigen and stimulate The production of "anti-idiotypic antibodies" (see Chapter 13). By cross-linking surface IMMUNOGLOBULINS on B cells, these antibodies can block their reactivity. In some animals, a large proportion of antibodies produced against certain antigens share a common idiotype; consequently, the suppression of this idiotype by anti-idiotypic antibodies can profoundly alter the immune response. However, such tolerance is partial, as it affects only those B cells bearing the specific idiotype.

In T cells, the idiotype is represented by the polymorphic Regions of the TCR α- and β-chains. TCR-specific regulatory cells, generated following vaccination with autoreactive T lymphocytes, TCR-derived peptides, or even TCR-encoding DNA, have been shown to prevent The Development of autoimmune processes.

Maintenance of tolerance in vivo. Antigen persistence is crucial for maintaining tolerance in vivo: when the concentration of antigen in the body drops below a certain threshold, reactivity recovers. If tolerance results from clonal deletion, the restoration of immune responsiveness depends temporally on the generation of new lymphocytes from progenitor cells. In this scenario, the tolerant state can be prolonged by performing a thymectomy. Conversely, if suppression is the underlying mechanism—as observed in immune deviation—tolerance may persist for a relatively long time.