Selective Immunointervention in Autoimmune Diseases: Lessons from Multiple Sclerosis

Abstract

Activation of peripheral T cells by foreign and self antigens is under stringent control by different mechanisms, both thymic and peripheral. Control of T cell reactivity is accomplished by three major types of mechanisms: 1) deletion, the physical elimination of T cells specific for a given antigen, 2) anergy, the functional incapacity of T cells to respond to antigen, 3) suppression, the inhibition of T cell function by a regulatory (suppressor) cell. Their failure may lead to autoimmune diseases.

The progress in understanding T cell activation, inactivation and modulation is being translated into strategies able to induce selective immunosuppression to treat different pathological situations, notably autoimmune diseases, allergies, and allograft rejection. The medical need for selective immunosuppression is very high, as the available immunosuppressive drugs are substantially inadequate because of limited efficacy, modest selectivity, and considerable toxicity. Key attack points for selective immunointervention have been identified: modulation of antigen recognition, co-stimulation blockade, induction of regulatory cells, deviation to non-pathogenic or protective responses, neutralization of proinflammatory cytokines, induction or administration of anti-inflammatory cytokines, and modulation of leukocyte trafficking.

All these forms of immunointervention have been successfully used to prevent and sometimes treat experimental autoimmune diseases. Based on these results, expectations have been raised for exploiting the same strategies to inhibit the activation of human autoreactive T cells. In this overview, we will examine recent advances towards immunointervention in multiple sclerosis (MS) as a paradigm for successes and failures of current immunotherapeutic approaches in human autoimmune diseases.