dc.contributor.author
Mertlitz, Sarah
dc.date.accessioned
2020-09-10T09:44:11Z
dc.date.available
2020-09-10T09:44:11Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/27793
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-27546
dc.description.abstract
For a variety of hematopoietic diseases, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option. Due to numerous improvements in the treatment procedure and the constant expansion of indications, the number of transplanted patients has increased rapidly during the last decades. Despite many achievements, the mortality rate after allo-HSCT is still high. The main and most severe complication after allo-HSCT is the graft- versus-host disease (GVHD) and up to 30% of allo-HSCT recipients die due to GVHD or GVHD-related side effects. GVHD is characterized by a systemic inflammatory reaction that is mainly mediated by alloreactive T cells. Alloreactive T cells cause severe tissue damage in main GVHD target organs colon, liver and skin via different cytotoxic mechanisms. All current treatment options aim at the suppression of T cell function, however, the inhibition of immune responses results in an increased risk for infections and tumor relapse. Therefore, there is a clear medical need in defining alternative targets for the development of therapies that act without hampering immune functions.
Recent work by us and others, identified an important role of the endothelium in the development of acute GVHD (aGVHD). However, the inhibition of vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, key mediators of angiogenesis, led to impaired hematopoietic engraftment, which is essential for a beneficial transplantation outcome. This thesis discusses two new approaches for the treatment of aGVHD after allo-HSCT. The first part of this work deals with an aspect that has not been studied in the context of aGVHD before, namely lymphangiogenesis. It is well known that lymph vessels carry out important immunologic functions and that lymphangiogenesis is involved in inflammation, cancer and graft rejection. However, the influence of lymphangiogenesis on inflammation can be beneficial or harmful and seems to depend on various factors such as the inflammatory trigger and the site of inflammation.
Evaluation of murine and human tissue samples showed a significant increase in lymph vessel density during aGVHD, confirming the clinical relevance of lymphangiogenesis in aGVHD. The inhibition of VEGFR3, a main regulator of lymphangiogenesis, revealed that reduced lymphangiogenesis attenuates clinical and histopathological features of aGVHD, without affecting malignant lymphoma growth.
In the second part of the thesis an alternative pathway of hemangiogenesis is investigated. Besides the prominent vascular endothelial growth factor (VEGF)/VEGFR signaling, an alternative pathway involved in angiogenesis is the transforming growth factor-beta (TGF-b) pathway. Depending on downstream signaling, the TGF-b pathway can initiate or inhibit angiogenesis. A study by Greenwood et al. identified the glycoprotein leucine-rich alpha-2-glycoprotein 1 (Lrg1) as regulator of the angiogenic switch in TGF-b signaling. Elevated serum levels of Lrg1 in samples from patients with inflammatory diseases further confirmed the assumption that Lrg1 is expressed under pathological rather than physiological conditions. The correlation between Lrg1-regulated TGF-b signaling and angiogenesis during aGVHD has not been investigated so far. We show that Lrg1 expression is increased in target organs during aGVHD and that the genetic loss of Lrg1 attenuates aGVHD. Using the additional inflammation models of experimental colitis and paw edema, we could also show that Lrg1 contributes to angiogenesis, altered vessel structure and increased inflammation in these disease models.
With this work, we were able to confirm the crucial role of the lymphatic and blood vascular system during aGVHD. We identified two novel factors that provide potential therapeutic targets to reduce aGVHD without interfering with anti-tumor immunity and immune reconstitution.
en
dc.format.extent
129 Seiten
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject
graft-versus-host disease
en
dc.subject
allogeneic hematopoietic stem cell transplantation
en
dc.subject
angiogenesis
en
dc.subject
lymphangiogenesis
en
dc.subject
leucine-rich alpha-2-glycoprotein 1
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie
dc.title
Angiogenesis in Graft-versus-Host Disease
dc.contributor.gender
female
dc.contributor.firstReferee
Penack, Olaf
dc.contributor.furtherReferee
Mutzel, Rupert
dc.date.accepted
2020-06-12
dc.identifier.urn
urn:nbn:de:kobv:188-refubium-27793-4
dc.title.translated
Angiogenese bei der Transplantat-gegen-Wirt Reaktion
de
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.note.author
Partial results of this thesis have already been published in: Lymphangiogenesis is a feature of acute GVHD, and VEGFR3 inhibition protects against experimental GVHD. Blood. 2017 Mar 30;129(13):1865-1875.
dcterms.accessRights.dnb
free
dcterms.accessRights.openaire
open access