In dieser Arbeit sollen die funktionellen Zusammenhänge zwischen Integrinrezeptoren und myokardialer Hypertrophieentwicklung am Maus-Model nach aortic-banding untersucht werden. Durch den Einsatz eines Integrin-alphaV/Beta3 und alphaV/beta5-Inhibitors (EMD 270179 der Fa. Merck) konnten gezielt diese Integrinrezeptoren gehemmt werden. Mittels morphologischen, histologischen, immunhistochemischen, biochemischen und bildgebenden Verfahren konnten bekannte Signalwegskaskaden reproduziert und eben auch eine mangelhaft einsetzende Hypertrophieentwicklung unter Integrin-Blockade nachgewiesen werden. Innerhalb von 2-7 Tagen (Untersuchungszeitraum) setzte in der Gruppe der behandelten Tiere eine myokardiale Dilatation ein, die mit einer deulich eingeschränkten linksventrikulären Funktion einherging. Nahezu die Hälfte der Tiere verstarben konsekutiv, während die unbehandelten Tiere deutlich bessere Überlebenschancen zeigten. Ein zur transthorakalen Aortenkonstriktion vergleichbares Ereignis beim Menschen wäre eine langjährig bestehende, unbehandelte arterielle Hypertonie oder eine Aortenstenose. Beides sind jedoch Ereignisse, die in der Regel nicht derart akut einsetzen, sondern sich entwickeln. Demnach wäre ein möglicher Einsatz beim Menschen nach entsprechenden Studien zur Ermittlung des optimalen Therapie-Fensters zu diskutieren. / We examined the functional connections between integrin-receptors and cardiac hypertrophy development in mouse model after aortic-banding. By application of an alphaV/Beta3 and alphaV/beta5-inhibitor (EMD 270179 Fa Merck) these integin-receptors could be restrained. By means of morphological, histologic, immunhistologic, biochemical and picture-giving procedures known signal way cascades could be reproduced. Also a faultily starting hypertrophy development under integrin-inhibition could be proved. Within 2-7 days (investigation period) in the group of the treated animals, cardiac dilatation started which was associated with a notable depressed leftventricular function. Nearly half of the animals died consecutively, while the untreated animals showed clearly better survival chances. One to aortic-banding comparable event in human would be a for many years existing, untreated arterial hypertension or an valvular aortic stenosis. Nevertheless, both are events which start as a rule not so urgently, but develop. Therefore, a possible application in humans would be to be discussed according to suitable studies to the inquiry of the optimum therapy window.

Regulatory T cells (Treg) play a crucial role in controlling immune homeostasis. Several inflammatory diseases including multiple sclerosis and inflammatory bowel disease have been associated with dysfunctional and/or reduced numbers of Treg. While several mechanisms of action have been discovered by which Treg can exert their function, disease-specific Treg requirements remain unknown. The Treg pool consists of highly diverse subpopulations, indicating that there is a potential to optimise Treg-targeted therapies if disease-relevant mechanisms can be established. Microarray data from our lab suggests a marked upregulation of the integrin αv as well as the IL-33 receptor ST2 in Treg retrieved from the inflamed central nervous system (CNS) during experimental autoimmune encephalomyelitis compared to peripheral lymphoid organs. These two molecules were further investigated within this PhD project with the aim to understand their role in Treg function during chronic inflammatory disease. αvβ integrins have been reported to be needed for effector T cell migration to inflamed sites through binding of extracellular matrix components and are involved in TGF-β activation by a variety of cell types. Conditional knockout mice lacking the integrin αv specifically in Foxpγ+ Treg were generated to address the role of αv integrins on regulatory T cells in inflammatory disease. αv-/- Treg showed a deficiency in activating latent TGF-β, but were able to suppress responder T cell proliferation in vitro as well as in vivo. αv-/- Treg were also able to migrate to the inflamed CNS during EAE and resolve disease. However, αv-/- Treg were detected at significantly lower numbers and proportions in the inflamed gut during a curative T cell transfer model of colitis; this led to a quantitative impairment in the ability of αv-/- Treg to cure colitis when compared to wild-type (WT) Treg. Whether this is a deficit in migration, survival, proliferation, or Foxp3 stability, remains to be investigated. IL-33 acts as an alarmin and is best studied as a cytokine released upon tissue damage that induces a potent type 2 immune response by acting on a multitude of immune cells. Expression of the IL-33 receptor ST2 on Treg has recently been associated with positive metabolic parameters in visceral adipose tissue, protection from gut inflammation, and tissue-restorative function in other inflamed tissues such as injured muscle or lung. This project showed that in steady state, ST2+ Treg expressed high levels of several markers which have been associated with potent regulatory function. When stimulated in vitro, ST2+ Treg showed a better survival and expansion rate compared to their ST2- counterparts, even more so in the presence of IL-33. T-bet deficiency in Treg resulted in an increased ST2+ Treg pool, and T-bet-associated cytokine IFN-γ was found to antagonise IL-33-induced expansion of the ST2+ Treg pool in a T-bet-independent manner. When ST2+ and ST2- Treg were tested for their respective suppressive capacity in vivo, ST2+ Treg were able to suppress responder T cell expansion despite being found only at low numbers in secondary lymphoid organs compared to ST2- Treg. However, in a curative model of T cell transfer colitis, ST2+ Treg were less capable of controlling the ongoing immune response than ST2- Treg. A possible explanation for the superiority of ST2- Treg in this setting can be found in the fact that injected ST2- Treg acquired a distribution of ST2 expression reminiscent of WT Treg over the course of disease. On the other hand, an increased starting pool of ST2+ Treg as occurs in T-bet-/- Treg significantly enhanced the capacity of Treg to control colitis compared to WT Treg. In conclusion, both ST2- and ST2+ Treg are likely to have a distinct, non-redundant role in suppressing T cell activation in secondary lymphoid organs and controlling ongoing inflammation in peripheral tissue, respectively.