dc.contributor.author | Aurelius, Johan | |
dc.date.accessioned | 2012-05-25T07:59:42Z | |
dc.date.available | 2012-05-25T07:59:42Z | |
dc.date.issued | 2012-05-25 | |
dc.identifier.isbn | 978-91-628-8481-9 | |
dc.identifier.uri | http://hdl.handle.net/2077/28967 | |
dc.description.abstract | This thesis aimed to define the role of reactive oxygen species (ROS), produced by the NADPH oxidase of myeloid cells, in the regulation of lymphocyte function with focus on ROS-induced dysfunction of natural killer (NK) cells and T lymphocytes in myeloid leukemia. In Paper I, a novel mechanism is presented by which specifically activated T lymphocytes evade inactivation by ROS after antigen presentation. Antigen-presenting dendritic cells were found to induce ROS-neutralizing thiols on the surface of antigen-specific T cells, but not on T cells that lacked antigen specificity. These findings may explain why antigen-specific T cells remain viable under conditions of oxidative stress. Paper II shows that subsets of leukemic cells recovered from patients with acute myeloid leukemia (AML) produce and release ROS via a membrane-bound NADPH oxidase, and that ROS-producing leukemic cells initiate a PARP-1-dependent pathway of cell death (parthanatos) in NK cells and T cells. The results presented in Paper III demonstrate that treatment of AML patients with a NADPH oxidase inhibitor (histamine dihydrochloride) was preferentially efficacious among patients with monocytic leukemias (FAB classes M4 and M5), in which cells of the leukemic clone expressed a ROS-producing NADPH oxidase and functional histamine H2 receptors. The results presented in Paper IV imply that malignant cells recovered from patients with chronic myeloid leukemia utilize the ROS/PARP-1 axis to induce NK cell parthanatos and that PARP-1 inhibition maintains functions of T cells and NK cells under conditions of oxidative stress. Paper V aimed to define the intracellular pathways of ROS-induced PARP-1 activation with ensuing cell death in lymphocytes. The results suggest that the mitogen-activated protein kinase ERK1/2 is involved in ROS-induced signal transduction and that ERK1/2 is activated upstream of PARP-1 in ROS-dependent lymphocyte parthanatos. | sv |
dc.language.iso | eng | sv |
dc.relation.haspart | I. Martner, A; Aurelius, J; Rydström, A; Hellstrand, K; Thorén, FB. Redox remodeling by dendritic cells protects antigen-specific T cells against oxidative stress.
J Immunol 2011;187 6243-6248.
::PMID::22095713 | sv |
dc.relation.haspart | II. Aurelius, J; Thorén, FB; Akhiani, A; Brune, M; Palmqvist, L; Hansson, M; Hellstrand, K; Martner, A. Monocytic AML cells inactivate anti-leukemic lymphocytes: role of NADPH oxidase/gp91phox expression and the PARP-1/PAR pathway of apoptosis. Blood 2012; Prepublished online May 1, 2012;
::doi::10.1182/blood-2011-11-391722 | sv |
dc.relation.haspart | III. Aurelius, J; Martner, A; Brune, M; Palmqvist, L; Hansson, M; Hellstrand, K; Thorén, FB. Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells.
Submitted 2012 | sv |
dc.relation.haspart | IV. Aurelius, J; Martner, A; Romero, AI; Riise, RE; Palmqvist, L; Brune, M; Hellstrand, K; Thorén FB. Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent inactivation and cell death in lymphocytes.
Submitted 2012. | sv |
dc.relation.haspart | V. Akhiani, AA; Aurelius, J; Movitz, C; Hellstrand, K; Thorén FB. Reactive oxygen species trigger ERK pathway-dependent parthanatos in cytotoxic lymphocytes.
Submitted 2012. | sv |
dc.subject | Acute myeloid leukemia | sv |
dc.subject | Immunosuppression | sv |
dc.subject | Immunotherapy | sv |
dc.subject | Reactive oxygen species | sv |
dc.subject | PARP-1 | sv |
dc.subject | NK cells | sv |
dc.subject | T cells | sv |
dc.title | Mechanisms of leukemia-induced immunosuppression | sv |
dc.type | text | eng |
dc.type.svep | Doctoral thesis | eng |
dc.gup.mail | johan.aurelius@gu.se | sv |
dc.type.degree | Doctor of Philosophy (Medicine) | sv |
dc.gup.origin | University of Gothenburg. Sahlgrenska Academy | sv |
dc.gup.department | Institute of Biomedicine. Department of Infectious Medicine | sv |
dc.gup.defenceplace | Torsdagen den 7 juni, kl 09.00 i hörsal Tor Bjurström, Medicinaregatan 3B. | sv |
dc.gup.defencedate | 2012-06-07 | |
dc.gup.dissdb-fakultet | SA | |