'Dendritic cells for immunity and tolerance', Zwi N. Berneman

Title: Dendritic cells for immunity and tolerance

Speaker: Prof. Zwi N. Berneman, MD PhD FRCP - Antwerp University Hospital and University of Antwerp, Antwerp, Belgium

Abstract:

Dendritic cells (DC) can be considered as the conductors of the immune system. They are specialized in antigen presentation and in stimulating immune responses, leading to immunity or in inhibiting them, leading to tolerance. Following internalization and digestion, pieces of antigenic proteins (epitopes) are presented on the surface of DC, where they are bound on major histocompatibility complex (MHC) proteins, also designated as HLA (human leucocyte antigens) in humans. Antigen epitopes that are presented on the surface of DC in the context of MHC class I molecules (HLA-A, -B or -C) stimulate CD8+ cytotoxic T-lymphocytes, while epitopes presented in  the context of MHC class II (HLA-DP, -DQ or -DR) have an influence on stimulatory CD4+ T-helper lymphocytes and inhibitory CD4+ regulatory T-cells (Treg). The T-cell receptors of T-lymphocytes interact with DC by specifically binding to the MHC/antigen epitope complex. The process of antigen presentation is accompanied by the stimulation or inhibition of the activity of T-lymphocytes through the interaction between membrane proteins of DC and T-cells and through the secretion of cytokines. DC are present in the blood and in many organs, where they perform a sentinel function and where they stimulate immunity if danger signals  (e.g. microbial products) are present. If no such danger signals are present, the DC will usually not stimulate immunity and will promote tolerance; this is an important mechanism for avoiding immunity against self-antigens, i.e. auto-immunity. DC can be cultured out of CD34+ hematopoietic progenitor cells or out of peripheral blood monocytes. The latter method is the preferred mode for clinical use. There are different ways to load DC with antigens; examples are peptide pulsing or electroporation of mRNA encoding antigens. The crucial importance of DC in the antigen-specific regulation of immunity and tolerance, makes them interesting instruments in the fight against cancer, chronic viral infections and auto-immunity. Immunogenic DC are being used in the fight against cancer, where they are intended to stimulate cytotoxic T-lymphocytes to lyse tumoral cells in a tumor-associated antigen-specific manner. In clinical trials that have been performed in cancer, an improved patient survival has been observed in general, although tumor reduction is only seen in a minority of patients. In a trial we conducted in 30 patients with acute myeloid leukemia, a demonstrable antileukeumic effect was seen in 8 patients and a possible effect in 8 other patients. The clinical use of tolerogenic DC is not as widespread, but trials have been conducted in rheumatoid arthritis and type 1 diabetes and a trial in multiple sclerosis is underway. Multiple sclerosis is an auto-immune disorder, affecting the myelin sheath of nerve cells in the central nervous system. While it is clear that auto-immune T-lymphocytes, directed against myelin antigens, play a role in the condition, there is increasing evidence that there are also abnormalities in the DC compartment, which may play an important role in driving the disease.