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Die akute Graft-versus-Host Erkrankung (GvHD), insbesondere die Darm GvHD, stellt weiterhin eine der Hauptursachen für Mortalität und Morbidität nach allogener SZT dar. Aktivierte, alloreaktive Spender T-Zellen infiltrieren dabei über die Blutbahn die intestinale Lamina Propria. Erst kürzlich konnten wir zeigen, dass neben der vaskulären Migration ein Teil der Spender T-Zellen auch direkt aus den PP in die angrenzende Lamina Propria migrieren. Um Faktoren, die diese direkte Migration fördern, zu untersuchen und die direkt migrierenden T-Zellen genauer zu charakterisieren, verwendeten wir ein MHC-inkompatibles Mausmodell zur Induktion einer akuten GvHD. Durch RNA Sequenzierung und Massenspektrometrie lasermikrodissezierter Darmschleimhautproben konnte eine starke Expression der Chemokine CXCL9, CXCL10, CXCL11, CCL3, CCL4 und CCL5 während der akuten intestinalen GvHD aufgezeigt werden. Neben CCL4 und XCL1 wiesen verschiedene Faktoren der T-Zellaktivierung, wie CD3ζ, LAT, Lck und ZAP70, sowie Faktoren der zytoskelettalen Reorganisation, wie Dock2, Coro1α und Parvin-γ, eine vermehrte Expression insbesondere nahe der PP auf. Die Expression der migrationsfördernden Faktoren Coro1α und Parvin-γ in Spender T-Zellen nahe der PP konnte anschließend mittels histologischen Immunfluoreszenzfärbungen bestätigt werden. Durchflusszytometrische Analysen konnten weiterhin eine vermehrte Expression von CCR5, CCR9 und Intgerin α4β7 auf den vornehmlich Tbet+ Spender T-Zellen nahe der PP nachweisen. Funktionelle in vitro Migrationsversuche zeigten abschließend, dass in vivo aktivierte Spender T-Zellen eine gerichtete Migration in Richtung auf CXCL11 und zu späterem Zeitpunkt auch auf CCL4 vollziehen können. Zusammenfassend zeigt diese Arbeit die Bedeutung zahlreicher Chemokine für das sequenzielle T-Zell-Homing während der akuten intestinalen GvHD. Neben der insbesondere durch Faktoren der zytosekeletalen Reorganisation vermittelten amoeboiden Migration kann auch eine mesenchymale Fortbewegung über Faktoren wie CCR5, CCR9 und Integrin α4β7 die direkte Migration der T-Zellen fördern. Den direkt migrierenden vornehmlich TH1 polarisierten Zellen folgen weitere, CD27 und Integrin αLβ2 exprimierende, zytotoxische T-Zellen aus der Blutbahn. Die direkt migrierenden Zellen könnten als Initiator und Potentiator der intestinalen T-Zell Infiltration wirken und müssen für zukünftige therapeutische Strategien nicht nur der Darm GvHD, sondern der intestinalen Inflammation im Allgemeinen mitberücksichtigt werden. / Acute graft-verus-host disease (GvHD), especially intestinal GvHD, remains one of the main causes of mortality and morbidity after allogeneic hematopoietic stem cell transplantation. In this process activated alloreactive donor T cells infiltrate the intestinal lamina propria via the bloodstream. Our group could recently show that besides the vascular migration route some donor T cells migrate directly from the Peyer’s patches into the adjacent lamina propria. To investigate factors that could promote such a direct migration, and to characterize these direct migrating T cells we applied a major mismatch mouse model to induce acute GvHD. Using RNA sequencing and mass spectrometry of lasermicrodissected lamina propria samples, we detected a strong upregulation of the chemokines CXCL9, CXCL10, CXCL11, CCL3, CCL4 and CCL5 during acute intestinal GvHD. Alongside CCL4 and XCL1, several factors of T cell activation, such as CD3ζ, LAT, Lck und ZAP70, as well as factors of cytoskeletal reorganization, such as Dock2, Coro1α und Parvin-γ, showed higher expression near the Peyer’s patches. Subsequently, we validated the expression of Coro1α and Parvin-γ on donor T cells near the Peyer’s patches with histological immunofluorescence stainings. Flow cytometry analysis further revealed high expression of CCR5, CCR9 and Intgerin α4β7 on the predominantly Tbet+ donor T cells near the Peyer’s patches. Conclusively, in vitro migration assays showed that in vivo activated donor T cells can directly migrate towards CXCL11 and subsequently also towards CCL4. The present study shows the relevance of several chemokines for the sequential T-cell homing during acute intestinal GvHD. Besides the amoeboid migration mode, which is particularly driven by cytoskeletal reorganization, a mesenchymal movement using factors, such as CCR5, CCR9 and Integrin α4β7, can promote the direct migration of donor T cells. The directly migrating cells, which are predominantly of a TH1 phenotype, are followed by cytotoxic T cells, expressing CD27 and Integrin αLβ2 (LFA-1), from the systemic circulation. Thus, these directly migrating cells may act like an initiator and potentiator for the intestinal T cell infiltration and must be considered for new therapeutic strategies not only of GvHD but of intestinal inflammation in general

Nyckeln i att utveckla ett bra flerspelar-spel ligger i spelets möjlighet till samarbete. Det är därför viktigt att veta hur olika spelsätt skiljer sig åt ur ett samarbetsperspektiv. Tidigare forskning har endast studerat samarbete för en given spelstil, till exempel spelare som möter andra spelare eller spelare som möter datorstyrda spelare, och har inte gjort någon direkt jämförelse mellan dessa. Bristen kring detta område har inspirerat till den aktuella undersökningen, som ämnat att undersöka eventuella skillnader på samarbete i spelet World of Warcraft. Det har utförts ett antal experiment, där deltagare fått möjligheten att spela World of Warcraft i slumpmässiga grupper. Dessa experiment har observerats för att analysera olika utslag som uppstått i samarbetet gentemot bestämda bedömningskriterier. Undersökningen har visat på stora skillnader i samarbete och har även visat vikten av social kompetens när det kommer till att interagera med sina medspelare. / The key to developing a good multiplayer game lies in the possibilities for cooperation. Therefore it is important to know how different playstyles differ from a collaborative perspective. Previous research has only studied cooperation within a given playstyle, such as player versus player or player versus environment and has not made a direct comparison between different playstyles. The lack of information about this topic is the inspiration for this study, which examines the difference in collaboration between the aforementioned playstyles in the game World of Warcraft. A number of experiments were carried out in which randomized groups of participants played the game World of Warcraft. The results of these experiments have been analyzed according to specific criteria and show large differences in cooperation as well as the importance of players’ social skills when interacting with other members of a team.

The goal of this thesis is to enable a robot to actively collaborate with a person to move an object in an efficient, smooth and robust manner. For a robot to actively assist a person it is key that the robot recognizes the actions or phases of a collaborative tasks. This requires the robot to have the ability to estimate a person’s movement intent. A hurdle in collaboratively moving an object is determining whether the partner is trying to rotate or translate the object (the rotation versus translation problem). In this thesis, Hidden Markov Models (HMM) are used to recognize human intent of rotation or translation in real-time. Based on this recognition, an appropriate impedance control mode is selected to assist the person. The approach is tested on a seven degree-of-freedom industrial robot, KUKA LBR iiwa 14 R820, working with a human partner during manipulation tasks. Results show the HMMs can estimate human intent with accuracy of 87.5% by using only haptic data recorded from the robot. Integrated with impedance control, the robot is able to collaborate smoothly and efficiently with a person during the manipulation tasks. The HMMs are compared with a switching function based approach that uses interaction force magnitudes to recognize rotation versus translation. The results show that HMMs can predict correctly when fast rotation or slow translation is desired, whereas the switching function based on force magnitudes performs poorly.