UCSF

Autoimmune disease results from the dysregulation of basic tolerogenic processes designed to control self/non-self-discrimination. Approaches to treat autoimmunity have focused historically on potent immunosuppressives that block the activation and expansion of antigen-specific T cells before they differentiate into pathogenic T cell responses. These therapies are very efficient in reducing clonal expansion and altering early signaling pathways. However, once the pathogenic responses are established (i.e., autoimmunity), the interventions are less effective on activated and differentiated T cell subsets (including memory T cells) or acting in the presence of an inflammatory milieu to abort immune responses at the target tissue and systemically. Moreover, the current immunotherapies require continuous use because they do not redirect the immune system to a state of tolerance. The continuous treatment leads to long-term toxicities and can profoundly suppress protective immune responses targeted at viruses, bacteria, and other pathogens. Over the past decade, there have been tremendous advances in our understanding of the basic processes that control immune tolerance. Among the most exciting has been the identification of a professional regulatory T cell subset that has shown enormous potential in suppressing pathologic immune responses in autoimmune diseases, transplantation, and graft vs. host disease. In this review, we summarize current efforts to induce and maintain tolerance in the autoimmune diabetes setting by using therapeutic vaccination with CD4+CD25+ regulatory T cells. Emphasis will be placed on approaches to exploit regulatory T cells either directly or through the use of anti-CD3 immunotherapy.

-------------------------------------------------------------------------------- Regulation of the immune response to self-antigens is a complex process that depends on maintaining self-tolerance while retaining the capacity to mount a robust immune response. T cells specific for these autoantigens are present in most normal individuals but are kept under control by multiple diverse peripheral tolerance mechanisms. For at least 30 years, there has been the notion that in addition to T cells that mediate effector immune responses to combat infections and mediate graft rejection, there are classes of regulatory/suppressor T cells that exist to control immunity (reviewed in ref. 1). Early on, CD8+ T cells were identified that suppress immune responses through their direct cytotoxicity on antigen-bearing cells or through cryptic suppressor factors that were poorly characterized (2). However, during this early period, there were already hints that the quintessential helper T cells subset, CD4+ T cells, also may have regulatory activity. North and Awwad (3) showed that depletion of CD4+ T cells by using anti-CD4 mAbs resulted in tumor rejection. This modern view of CD4+ regulatory T cells (Tregs) was enhanced by the observations by Sakaguchi et al. (4, 5) that the adoptive transfer of T cells depleted of CD4+CD25+ cells induced multiorgan autoimmunity in the recipient animals. These studies complemented ongoing efforts by a number of groups in England and France who demonstrated antigen-specific Treg populations in mice and rats (6–9). In fact, multiple investigators provided compelling data to support the existence of Tregs in rodents, especially in those animals that had undergone certain immunotherapeutic interventions in the allogeneic transplant or autoimmune setting. For example, populations of CD4+ peripheral T cells and thymocytes were shown to prevent induction of autoimmune thyroiditis in an antigen-specific manner (10). The Tregs were shown to be driven by peripheral autoantigen and could be extracted from mice maintaining long-term allografts. Most importantly, Gershon and Kondo (11), and subsequently Cobbold and Waldmann (8), developed the concept of infectious tolerance, where cells from tolerant animals could be transferred to naïve recipients suppressing not only the original antigen specificities but other antigens linked through the same antigen-presenting cells. However, progress in this area was slow and tedious, often fraught with skepticism in the community because of difficulty in defining the precise phenotype of these cells, their antigen specificity, and the mechanistic basis for the suppressive activity.