Glucocorticoids delivered by inorganic_organic hybrid nanoparticles mitigate acute graft_versus_host disease and sustain graft_versus_leukemia activity

Authors
TK Kaiser, H Li, L Robmann, SD Reichardt et al

Lab
Institute for Cellular and Molecular Immunology, University Medical Center G ottingen,G_ottingen, Germany

Journal
European Journal of Immunology

Abstract
Glucocorticoids (GCs) are widely used to treat acute graft-versus-host disease (aGvHD) dueto their immunosuppressive activity, but they also reduce the beneficial graft-versus-leukemia (GvL) effect of the allogeneic T cells contained in the graft. Here, we tested whether aGvHD therapy could be improved by delivering GCs with the help of inorganic–organic hybrid nanoparticles (IOH-NPs) that preferentially target myeloid cells. IOH-NPs containing the GC betamethasone (BMP-NPs) efficiently reduced morbidity, mortality, and tissue damage in a totally MHC mismatched mouse model of aGvHD. Therapeutic activity was lost in mice lacking the GC receptor (GR) in myeloid cells, confirming the cell type specificity of our approach. BMP-NPs had no relevant systemic activity but suppressed cytokine and chemokine gene expression locally in the small intestine, which presum-ably explains their mode of action. Most importantly, BMP-NPs delayed the development of an adoptively transferred B cell lymphoma better than the free drug, although the over-all incidence was unaffected. Our findings thus suggest that employing IOH-NPs could diminish the risk of relapse associated with GC therapy of aGvHD patients while still allowing to efficiently ameliorate the disease.