Manipulation of dendritic cells for tolerance induction in transplantation and autoimmune disease.

Dendritic cells (DC) constitute a complex system of uniquely well-equipped antigen-presenting cells that initiate and regulate immune responses. Extensive recent studies have improved our understanding of DC development, differentiation, activation, and function. DC exist as distinct subsets that differ in their lineage affiliation, surface molecule expression, and biological function. These factors seem to determine the T-cell polarizing signals and type of T cell response-T helper 1, T helper 2, or T regulatory- induced by DC (1). Evidence has accumulated that DC play an important role in both central and peripheral tolerance via various mechanisms, including induction of T-cell anergy, immune deviation, T regulatory cell activity, and promotion of activated T-cell apoptosis. Although many of the details of the molecular basis of DC tolerogenicity have yet to be elucidated, emerging information suggests that costimulatory molecule deficiency, expression of death-inducing ligands (in particular Fas [CD95] ligand), microenvironmental factors (in particular anti-inflammatory/immunosuppressive cytokines), and inhibition of gene transcription regulatory proteins (e.g., nuclear factor-kappaB) can impart tolerogenic potential to DC (2). Manipulation of DC by control of their maturation and differentiation, or genetic engineering of these cells to express immunosuppressive molecules, offers potential for therapy of allograft rejection and autoimmune disease. In this brief overview, we outline principles and methods for generation of "tolerogenic" DC and outcomes that have been reported in experimental models. Space constraints limit literature citations.