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Angiogenesis during GVHD

Published article “Initiation of acute graft-versus-host disease by angiogenesis” on Blood Cover Vol 129, Issue 14: 1887-2038.
Published article “Initiation of acute graft-versus-host disease by angiogenesis” on Blood Cover Vol 129, Issue 14: 1887-2038.

An interesting novel therapeutic concept with potential simultaneous impact on tumor growth and inflammatory processes is the inhibition of Angiogenesis. We have demonstrated that the inhibition of inflammation-associated angiogenesis ameliorates GVHD by reducing the recruitment of tissue infiltrating leukocytes. Recently, we published data showing that angiogenesis precedes leukocyte infiltration in experimental models of inflammatory bowel disease and GVHD, implicating that angiogenesis has an active role during the initiation of inflammation. In further steps, we are investigating cellular and molecular mechanisms of initial angiogenesis after allo-HSCT. Eventually, we aim at translational development of anti-angiogenic therapies to simultaneously reduce GVHD and tumor growth after allo-HSCT. 

 

 

Lymphangiogenesis during GVHD

Increased Density of Lymphatic Vessels during GVHD. Anti-Lyve1 stained (green) colon sections demonstrate a higher lymph vessel density in recipients of an allo-HSCT as compared with recipients of a syn-HSCT

Lymph vessels play a crucial role for immune reactions in health and disease. The inhibition of lymphangiogenesis is an established therapeutic concept in oncology, which has entered clinical trials stage. During allogenic tissue transplantation the inhibition of lymphangiogenesis has been used to attenuate graft rejection. We are currently using murine allo-HSCT models and patient biopsies to demonstrate that acute GVHD is associated to lymphangiogenesis. We are studying the effect of monoclonal antibodies against vascular endothelial growth factor receptor 3 (VEGFR-3) on lymphangiogenesis, GVHD, tumor growth, immune reconstitution and survival in murine allo-HSCT models.

 

 

 

Cathepsin E and Dendritic Cell Motility during GVHD

Increased Ctse Expression in Colon during GVHD. Anti-Ctse stained (green) colon sections demonstrate more Ctse+ immune cells in colon tissue during GVHD as compared with syngeneic controls.

We are interested in improving our understanding about the molecular mechanisms in the initiation phase of GVHD. Several insights into inflammatory processes have been gained from recent research, which show that interactions between microbial associated molecules (pathogen associated molecular patterns, PAMPs) and innate immune receptors (pathogen recognition receptors, PRRs) control adaptive immune responses in inflammatory disorders. We are working on one mechanism that can better explain the connection between microbial products and inflammation. We are currently studying the role of Cathepsin E (Ctse), an aspartate protease known to cleave bacterial peptides for antigen presentation in dendritic cells (DCs), for GVHD. During experimental acute GVHD, we find infiltration by Ctse positive immune cells in target organs. In Ctse deficient allo-SCT recipients, we find ameliorated GVHD, improved survival and lower numbers of tissue infiltrating DCs. Our current data suggest that Ctse has a previously unrecognized role in regulating DC motility, which we are planning to study in more detail.

 

 

 

Effect of Green Tea on GVHD

Reduced Inflammation in GVHD Target Organs after EGCG Treatment. Shown are H&E stains of colon tissue. Lymphocyte infiltration is reduced after EGCG Treatment. CL: Crypt loss, CA: Crypt apoptosis

Recent research demonstrated that epigallocatechin gallate (EGCG), a component found in green tea leaves at a level of 25-35% at dry weight, may be useful in the inhibition of GVHD due to its immune modulatory, anti-oxidative and anti-angiogenic capacities. In murine allo-HSCT recipients treated with EGCG, we found significantly reduced GVHD scores, reduced target organ GVHD and improved survival. We are currently studying the underlying mechanisms of EGCG-mediated GVHD regulation.

 

 

 

Enhancement of Endothelial Regeneration and Endothelial Function during GVHD

Schematic involvement of endothelium during GVDH (Penack and Helms)

The endothelium is the first contact for immunological effector cells in the blood and key to the regulation of various inflammatory processes. Recent studies suggested that endothelial dysfunction and endothelial damage are critical factors for the development and severity of GVHD. Endothelial dysfunction during GVHD, as well as the mechanisms leading to endothelial dysfunction, have not been well characterized. In a collaborative research project between Charité Universitätsmedizin Berlin and Institut de Recerca contra la Leucèmia Josep Carreras / Hospital Clinic Campus Barcelona, we are planning to characterize endothelial damage and test strategies to enhance endothelial regeneration after allo-HSCT.

        

Use of Lycium barbarum polysaccharide (LBP) after allo-HSCT

Goji Berries, which are used to produce LBP

Although it has only been introduced in Western countries in recent years, Goji berry has been used for thousands of years in China, both as a culinary ingredient and medicinally. It has been reported that Goji berry contains natural anti-inflammatory, anti-bacterial and anti-fungal compounds. Their powerful antioxidant properties and Lycium barbarum polysaccharides (LBP) help to boost the immune system. It’s no wonder then, that in traditional Chinese medicine they are renowned for increasing strength and longevity. It has been reported that LBP has anticancer effect and could induce the apoptosis of human cancer cells. It was also found that macrophages, rather than T and B cells, are the principal immunostimulatory target cells of the LBP. We have established collaborations with different Chinese universities to study the mechanisms of the effect of LBP with our animal models.

                          

Memory Cells and the Vascular Niche after HSCT

BM Vasculature in a Murine GVHD Model. Shown are an anti-endomucin (yellow), anti-CD44 (red) and anti-CD4 (cyan) stains of the femoral bone. Nuclei are Dapi-stained (blue).

Two major obstacles to a more favorable therapeutic outcome of allo-HSCT are fatal infections and tumor relapse. Both complications are facilitated by long-term immune incompetence, which is known to be caused by HSCT. Mechanisms leading to HSCT-related long term immune incompetence are incompletely understood. Dr. Na’s group recently found, that acute GVHD affects thymus and bone marrow, leading to delayed T and B cell reconstitution. Memory cell deficiency after HSCT leads to a high susceptibility to fatal infections and therefore strategies to overcome this long-lasting immunodeficiency are required. Recently, it has been demonstrated that the BM is a reservoir for memory T and B cells, which are antigen-experienced immune cells crucial for immunity against a broad variety of pathogens. Memory T cells are maintained in close proximity to BM blood vessels suggesting endothelial cells to be part of the memory cell survival niche. In a collaborative research project between the research groups of Il-Kang Na and Olaf Penack, we aim to characterize the memory T and B cell reconstitution after syngeneic (syn) and allo-HSCT and to elucidate the role of the BM vasculature for the memory T and B cell survival in the BM. Furthermore, we will test immunotherapeutical and pharmacological strategies to improve the regeneration of the BM vasculature in order to facilitate accelerated seeding and maintenance of memory T and B cells into the BM and to provide thereby long-term immunity after HSCT.