Modulation of immune responses

In diseases generated by an excessive or inappropriate immune response, immunosuppressive drugs provide the basis of current treatment regimens. However, drugs such as cyclophosphamide, methotrexate and corticosteroids have broad-spectrum activity, and therefore disrupt the function of many cell types. Furthermore, prolonged treatment with many of these drugs is associated with an increased incidence in B cell lymphomas and other malignant disease.

Cyclosporin, which is derived from a soil fungus, and the structurally dissimilar drug FK506 are now used to suppress the rejection of allografts. They both act by binding to calcineurin and inhibiting signalling pathways leading to IL-2 synthesis.

Antilymphocyte serum has beneficial effects in acute graft rejection but, due to its lack of specificity for only alloreactive cells, has limited value. The role of antibodies reactive with TCR, coreceptors (CD4 and CD8), costimulatory molecules (CD80 and CD86) and adhesion molecules in modulating autoimmune disease and graft rejection are being investigated in experimental models. In clinical trials the therapeutic effects of anti-CD4 antibodies have been generally limited.

The potential to prevent disease by inducing immunity through vaccination remains an important area of research in medicine. There is a need both to generate vaccines for those diseases where at present none exists such as AIDS, and to improve the efficacy of other vaccines that are currently in use, e.g. for influenza.

Of the different features required for an ideal vaccine (see the first information box), safety and protection are perhaps the most important elements.

The design of potential vaccines is greatly influenced by the qualitative nature of the immune response (cell-mediated or humoral immunity) required to mediate protection. To meet these specific needs, different approaches have been adopted (see the second information box). Furthermore, the route of administration may also be important and, where down-regulation of the immune response is required, delivery via the mucosal surfaces of the gastrointestinal and respiratory tracts is an effective way of inducing immunological tolerance.