title: CD40/CD154 interactions at the interface of tolerance and immunity.
abstract: Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
authors.forename: Lamis Z
authors.initials: LZ
authors.lastname: Jarvinen
authors.forename: Evan F
authors.initials: EF
authors.lastname: Lind
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology; D018448:Models, Immunological; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand