Therapeutic vaccination using CD4CD25 antigen-specific regulatory T cells

Autoimmune disease results from the dysregulation of basictolerogenic processes designed to control self non-self-discrimi-nation. Approaches to treat autoimmunity have focused histori-cally on potent immunosuppressives that block the activation andexpansion of antigen-specific T cells before they differentiate intopathogenic T cell responses. These therapies are very efficient inreducing clonal expansion and altering early signaling pathways.However, once the pathogenic responses are established (i.e.,autoimmunity), the interventions are less effective on activatedand differentiated T cell subsets (including memory T cells) oracting in the presence of an inflammatory milieu to abort immuneresponses at the target tissue and systemically. Moreover, thecurrent immunotherapies require continuous use because they donot redirect the immune system to a state of tolerance. Thecontinuous treatment leads to long-term toxicities and can pro-foundlysuppressprotectiveimmuneresponsestargetedatviruses,bacteria, and other pathogens. Over the past decade, there havebeen tremendous advances in our understanding of the basicprocessesthatcontrolimmunetolerance.Amongthemostexcitinghas been the identification of a professional regulatory T cellsubset that has shown enormous potential in suppressing patho-logic immune responses in autoimmune diseases, transplantation,and graft vs. host disease. In this review, we summarize currentefforts to induce and maintain tolerance in the autoimmunediabetes setting by using therapeutic vaccination with CD4 CD25regulatoryTcells.Emphasiswillbeplacedonapproachestoexploitregulatory T cells either directly or through the use of anti-CD3immunotherapy.