Antigen-specific immunotherapy of autoimmune and allergic diseases

Abstract

Nearly a century has passed since the first report describing antigen-specific immunotherapy (antigen-SIT) was published. Research into the use of antigen-SIT in the treatment of both allergic and autoimmune disease has increased dramatically since, although its mechanism of action is only slowly being unravelled. It is clear though, from recent studies, that success of antigen-SIT depends on the induction of regulatory T (T reg) cell subsets that recognise potentially disease-inducing epitopes. The major challenge remaining for the widespread use of antigen-SIT is to safely administer high doses of immunodominant and potentially pathogenic epitopes in a manner that induces T cell tolerance rather than activation. This review illustrates that intelligent design of treatment agents and strategies can lead to the development of safe and effective antigen-SIT.

Figure 1

Self-regulatory properties of effector Th populations through chronic/repetitive stimulation. Differentiation of naïve CD4⁺ T cells into effector Th1, Th2 and Th17 populations is well established. Recent evidence from viral-infection and helminth-infection models, as well as numerous allergen-specific and autoantigen-specific peptide therapy trials, suggests that upregulation of IL-10 occurs during chronic or repetitive stimulation and can serve as a self-limiting mechanism [43,44^•]. Shown are the potential cytokines/transcription factors/signalling molecules that mediate the switch from effector T (T eff) to IL-10-secreting regulatory populations. Note that Th2 cells produce IL-10 upon initial differentiation, and while evidence does suggest that IL-10 helps host survival during helminth infection [44^•], whether this is a general feature of well-differentiated Th2 cells remains unclear.

Figure 2

Dosing strategy for antigen-SIT. Repeated administration of high-dose/affinity antigen has the potential to induce the highest level of anergy and tolerance, but the first few treatments may induce acute and sometimes severe side effects. Low-dose antigen does not carry a risk of side effects, nor does it induce robust tolerance. The low dose does, however, allow for the gradual increase of the dose without the adverse effects normally associated with the higher dose.