Project Summary

Recent evidence has challenged the concept that acute graft-versus-host disease (GvHD) is confined to the classical target organs intestines, liver and skin by revealing central nervous system (CNS) injury caused by donor derived alloreactive T cells resulting in CNS-GvHD. To cause disease alloreactive T cells need to be activated and our preliminary data indicate that this could be via CNS residing myeloid cells which we found to be increased in humans and mice that suffered from GvHD. Therefore, we plan to clarify the role of myeloid cell populations during CNS-GvHD. We plan to answer the following questions: 1. Are myeloid cells functionally involved in CNS-GvHD and what is their origin during GvHD (tissue residing or recruited)? 2. What is the role of TGF-β activated kinase-1 (TAK1) for microglia during GvHD? 3. Which microglia cells are pro- and which are anti-inflammatory in CNS-GvHD (myeloid suppressor cells vs. DCs)? 4. Can CNS-GvHD related behavior changes in the animals be reversed by adoptive transfer of anti-inflammatory myeloid cell populations? 5. Which myeloid cell populations are found in the CNS of patients that died because of GvHD? With these studies we will clarify the role of different myeloid cells in the pathogenesis of CNS-GvHD.