Flynn, Ryan Patrick2015-04-082015-04-082014-08https://hdl.handle.net/11299/171096University of Minnesota Ph.D. dissertation. August 2014. Major: Microbiology, Immunology and Cancer Biology. Advisor: Dr. Bruce R. Blazar, M.D. 1 computer file (PDF); ix, 170 pages.Allogeneic hematopoietic stem cell transplantation is a potential cure for many malignant diseases. However, the possibility of chronic Graft-Versus-Host Disease (GVHD) is a major obstruction to the therapeutic results. Development of novel therapies has been hindered by an incomplete knowledge of the mechanism of disease. This is in part due to a lack of relevant mouse models. Using a new murine model of chronic GVHD we shed light on the mechanism of disease as well as proposed novel therapeutics that could be beneficial for the treatment of chronic GVHD. First, we demonstrate that B cells derived from the donor bone marrow are necessary for the progression of disease and that these B cells had to produce class-switched antibodies. The production of class-switched antibody is dependent on the germinal center reaction. The need for the germinal center is further highlighted by the requirement for the presence of T follicular helper cells. These specialized cells promote the germinal center reaction by providing survival signaling to B cells through the IL-21 cytokine and ICOS and CD40 costimulatory molecules. We further provide evidence that T follicular helper cells and the germinal center reaction are necessary by demonstrating that therapeutic depletion of B cells during active chronic GVHD is unable to prevent the progression of disease. Finally, we demonstrate the importance of B cell signaling following antigen stimulation. Inhibition of the B-cell signaling molecule Syk directly down-stream of B-cell receptor signaling is sufficient to prevent the progression of chronic GVHD. Collectively this work identifies important B-cell survival signals that are necessary for the development of chronic GVHD.enChronic GVHDGerminal centersGraft-versus-host diseaseT follicular helper cellsMicrobiology, immunology and cancer biologyThesis or Dissertation