The role of beta-defensins in allogeneic transplantation

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Beta-defensins are small antimicrobial peptides encoded by the host playing an important role in antimicrobial innate immunity. In addition to the direct microbicidal effects of these polypeptides it became evident that members of the beta-defensin family have the capacity to promote local innate inflammatory and systemic adaptive immune responses. These functions seem to be mediated by their ability to act as chemokines and activators of monocytes, mast cells, APCs, and lymphocytes. Interestingly, the expression of several betadefensins is induced by intracellular pattern recognition receptors (NODs), while at the same time single nucleotide polymorphisms (SNPs) in NOD genes are associated with severe graft versus host disease (GvHD) and higher transplantation-related mortality in patients after allogeneic transplantation. We assume that beta-defensin expression plays an important role in bone marrow transplantation (BMT) by interacting with specific chemokine receptors (e.g. CCR6 and/or CCR2). The aim of this study is to identify and functionally characterize the role of beta-defensins and beta-defensin receptors in allogeneic transplantation. The correlation of beta-defensininduced expression by NODs and the negative association of SNPs in NOD genes observed in patients after allogeneic transplantation will be tested using allogeneic bone marrow transplantation models in mice. Furthermore, the ability of beta–defensins to promote local innate inflammatory and systemic adaptive immune responses after allogeneic transplantation will be evaluated. Mice transgenic for beta-defensin expression will be analyzed in detail in order to characterize the cellular and molecular mechanisms induced by beta-defensins. As a translational approach, human beta-defensin expression will be analyzed 1) in GvHD target tissues and in bronchioalveolar fluid of BMT patients, and 2) in serum of liver transplant recipients.