Treatment of acute Graft-versus-Host Disease using inorganic-organic hybrid nanoparticles

by Tina Katarina Kaiser
Doctoral thesis
Date of Examination:2019-11-27
Date of issue:2019-12-04
Advisor:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Lutz Walter
Referee:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Hubertus Jarry
Referee:Prof. Dr. Michael P. Schön
Persistent Address: http://dx.doi.org/10.53846/goediss-7756

 

 

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Abstract

English

Acute Graft-versus-Host Disease (aGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation, which is induced by donor T cells that become stimulated after recognizing recipient proteins as foreign. Glucocorticoids (GCs) are the standard first-line therapy of aGvHD due to their strong immunosuppressive effects mediated via the ubiquitously expressed glucocorticoid receptor (GR). While GC therapy is believed to mainly target T cells, our results show that radioresistant recipient myeloid cells are also crucial. This was demonstrated by using genetically engineered mice lacking the GR in myeloid cells and thus being refractory to GCs. These GRlysM mice were unable to limit systemic cytokine secretion during aGvHD leading to a premature death of the mice. Considering the importance of myeloid cells, we tested the potential of a targeted delivery of GCs to this cell type by using inorganic-organic hybrid nanoparticles (IOH-NPs). Our results demonstrate that IOH-NPs were preferentially taken up by macrophages, internalized via macropinocytosis, and localized to the lysosomal compartment. Magnetic resonance imaging and analysis by Inductive Coupled Plasma-Mass Spectrometry further revealed that IOH-NPs were rapidly cleared from the peritoneal cavity after intraperitoneal injection in mice and thereafter accumulated in abdominal organs. When we induced aGvHD in mice and treated them with IOH-NPs containing the GC betamethasone (BMP-NPs), the disease was ameliorated to a similar extent as by the free drug by limiting tissue destruction in the jejunum. The therapeutic effects were abrogated when GRlysM mice were treated with BMP-NPs, confirming that this nanoformulation mainly acted via macrophages in vivo. Nevertheless, BMP-NPs employed partially different mechanisms and reduced the local production of pro-inflammatory cytokines in the first place. Further in vivo analyses revealed that despite their cell type specificity, typical metabolic side-effects of GCs in muscle, liver and bone could not be circumvent by the use of IOH-NPs. Collectively, this work reveals an important role of myeloid cells as targets of GC therapy of aGvHD and suggest that specifically targeting these cells might improve certain aspects of this therapeutic regimen.
Keywords: aGvHD; inorganic-organic hybrid nanoparticles; glucocorticoid receptor; myeloid cells; cytokine storm; targeted delivery; GC side-effects
 
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