Polymorphisms within innate immunity receptors (NOD2/CARD15, TLR5, ATG16L1) have been associated with more severe graft-versus host disease (GvHD) and a worse outcome in allogeneic stem cell transplantation. Recent immunohistological studies from our group suggest that polymorphisms within innate immunity receptors (NOD2/CARD15, TLR5) affect the interactions between antigen presenting cells (APC) and CD4 cells. As APC are of crucial importance for the development of GvHD and their early activation determines development of alloreaction versus tolerance, we will analyze the influence of variations in Toll-like receptor (TLR) and intracytoplasmatic NOD-like receptor expression on the phenotype and function of APC. Furthermore, there is increasing evidence for specific and diverse functions of different APC populations within epithelial compartments. For this purpose we will: (1) investigate the composition and function of distinct APC populations in the skin of donors and patients with or without NOD2/CARD15 and TLR5 polymorphisms ex vivo, (2) analyze the phenotype and function of monocyte-derived dendritic cells from healthy donors with or without NOD2/CARD15 and TLR5 polymorphisms after stimulation with TLR ligands and NOD ligands in vitro, and (3) investigate the effect of NOD ligands on the expression of vitamin D and vitamin A metabolizing enzymes in monocyte-derived dendritic cells; both vitamins are produced by APC, are involved in T cell homing and can influence the generation of T regulatory cells (Treg). It is expected that these studies will contribute to the development of new and more selective approaches to interfere therapeutically with TLR and NOD pathways in APCs. Pharmacological modulation of APCs could re-balance T helper cell populations and is a promising approach for therapeutic immunomodulation.
