Antigenic substances other than self antigens have to be tolerated by the immune system.
In eutherian mammals, the fetus contains antigens from the father that are foreign for the mother, and the placenta allows these antigens to enter the maternal circulation and maternal antibodies to enter the fetus. Nevertheless, the paternal antigens do not elicit harmful immune responses in the mother, so the fetus is not rejected. Regulatory T cells and other mechanisms are responsible for fetal tolerance.
Commensal microbes are abundant in the gut, skin, and other tissues but also do not elicit immune responses despite being foreign. There are several reasons for this lack of immunogenicity. Many of these microbes cannot invade epithelial barriers and therefore may not be accessible to the adaptive immune system. These microbes also induce and activate Tregs, which prevent the development of effector and memory cells.
Foreign antigens may be administered in ways that preferentially induce tolerance rather than immune responses. In general, protein antigens administered with adjuvants favor immunity, whereas repeated doses of antigens administered without adjuvants tend to induce tolerance. The likely reason for this is that adjuvants stimulate innate immune responses and the expression of costimulators on APCs, and in the absence of these second signals, T cells that recognize the antigen may become anergic or die or may differentiate into Tregs.
The oral administration of a protein antigen often leads to suppression of systemic humoral and cell-mediated immune responses to immunization with the same antigen. This phenomenon, called oral tolerance.
Therapeutic Tolerance Induction
Understanding how to induce tolerance by antigen administration may lead to the development of antigen-specific tolerance as a treatment strategy for immunologic diseases. This would avoid a problem with current therapies for autoimmune diseases and graft rejection, which are not antigen specific and suppress all immune responses, resulting in variable degrees of immune deficiency. Numerous clinical studies are underway to induce tolerance in autoimmune diseases and allergies in which the relevant antigen is known. The autoimmune diseases include type 1 diabetes (in which insulin is a target antigen), multiple sclerosis (MS, myelin proteins), and rheumatoid arthritis (in which citrullinated peptides are autoantigens). Several strategies are being tried.
• Repeated administration of small doses of immunodominant peptides derived from the self antigen, in aqueous form without adjuvants. It is expected that the antigen will be recognized in the absence of costimulation and will induce peripheral T-cell anergy or deletion or preferentially activate Tregs, but the clinical trials completed to date have not demonstrated efficacy. It is also unclear how effective this approach will be in inhibiting ongoing immune responses in patients. This approach has been used for many years to treat allergies (the process called allergy immunotherapy or peptide immunotherapy). It is effective in a subset of allergic patients, but how the treatment works is also not established.
• Administration of peptides derived from self antigens coupled to nonimmunogenic substrates such as nanoparticles and erythrocyte membranes. The idea is similar to aqueous antigen administration.
• Transfer or activation of Tregs has been mentioned previously.
• Costimulatory blockade refers to blocking B7 molecules using the drug CTLA-4-Ig. It is likely this treatment inhibits immune responses but does not induce long-lived tolerance.
Despite the promise of these approaches, there has so far been little success in resetting the immune system to prevent responses against autoantigens in patients with ongoing autoimmune diseases. The same approaches are being considered to block immune responses to viral vectors used to introduce genes to replace defective genes, and to prevent responses to proteins such as Factor VIII given to treat hemophilia A. There is, however, no tolerance inducing strategy that has been approved so far.
