Role of monocytes and Th17 cells in the pathogenesis of graft-versus-host disease - influence of S100 proteins and Hsp90

• Applicant: Professorin Dr. Ursula Holzer
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273124679

Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation. However, the pathophysiology of GvHD is not fully understood. Our group could demonstrate that in vivo activated monocytes of patients with acute or chronic GvHD induced higher levels of Th17 cells compared to monocytes of patients without GvHD. In the proposed project monocytes as well as monocyte-induced Th17 cells of patients with acute or chronic GvHD will be characterized. In autoimmune diseases it is known that the CD14+CD16+ proinflammatory monocyte subpopulation can be divided into two subgroups: CD14+CD16++ monocytes and CD14++CD16+ monocytes whereby the latter induces high levels of proinflammatory Th17 cells. In this project the percentage of these monocyte subpopulations will be determined and sorted in patients with and without acute or chronic GvHD. A subgroup of IL-17 producing T cells (Th17.1 cells) express the p-glycoprotein (multi-drug resistance type 1 protein (MDR1)) and are resistant to immunosuppression with glucocorticoids. Therefore, the sorted monocyte subpopulations will be analyzed in terms of induction of MDR-Th17 and MDR+Th17.1 cells. Additionally, the influence of immunoregulation e.g. regulatory T cells (Tregs), TGFbeta or glucocorticoids on monocyte-induced Th17 cells of patients with GvHD will be investigated. Correlating our results with the clinical course of the studied patients we would like to prove the hypothesis that patients with high risk for developing severe or chronic GvHD might be identified by elevated levels of CD14++CD16+ monocytes or Th17.1 cells. This may allow the implementation of risk stratified therapeutic approaches. Furthermore, the impact of S100 proteins as known amplifier of inflammation and their interplay with heat shock protein (Hsp) 90 will be investigated in monocytes. In our previous work, elevated levels of S100 proteins could be detected in the bowel tissue, stool and serum of patients with acute and chronic GvHD demonstrating the release of these phagocyte-specific proteins during GvHD. Stimulation of monocytes with S100 proteins was found to promote Th17 development which could be inhibited by blockade of Hsp90. Therefore, the intersection of the signaling pathways of S100 proteins and Hsp90 will be investigated by microarray analysis and verified on protein level in the planned study. The understanding of the mechanisms of activation and regulation of inflammatory cells in GvHD is essential for the identification of central factors underlying the destroying inflammation of this disease. Our results pave the way for novel specific therapeutic strategies, e.g. inhibition of Hsp90 in these often multimorbid patients.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Tobias Feuchtinger; Professor Dr. Peter Lang