Antigen Presentation and Inflammation in Allogeneic Bone Marrow Transplantation

Kate Ann Markey (2010). Antigen Presentation and Inflammation in Allogeneic Bone Marrow Transplantation , School of Medicine, The University of Queensland.

       
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Author Kate Ann Markey
Thesis Title Antigen Presentation and Inflammation in Allogeneic Bone Marrow Transplantation
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2010-12
Supervisor Dr Kelli PA MacDonald
Professor Geoffrey R Hill
Total pages 233
Total colour pages 7
Total black and white pages 216
Subjects 11 Medical and Health Sciences
Abstract/Summary Allogeneic bone marrow transplantation (BMT) is utilised as a curative therapy for haematological malignancies, predominantly leukaemia. The curative benefit of BMT lies in the graft-versus-leukaemia (GVL) effect, in which residual leukaemic cells are recognised by the incoming donor immune system and targeted for elimination via immunological means. Allogeneic BMT is however complicated by a high procedure-related mortality, with post-BMT death occurring due to relapse, infection and graft-versus-host disease (GVHD). GVHD develops to some extent in the majority (50-70%) of allogeneic BMT recipients and results in widespread immunological damage to host tissue, mediated by T and NK cells in the donor graft, as well as by inflammatory cytokines (e.g. TNF, IL-1). There are three key phases in GVHD pathogenesis: 1) initial host tissue damage secondary to pre-transplant conditioning which leads to an initial release of pro-inflammatory cytokines; 2) activation of donor T cells in the graft by both host and donor antigen presenting cells; and 3) the expansion of effector donor T cells and intensification of the inflammatory cytokine response. My work has focused on both the inflammatory cytokine and antigen presentation aspects of GVHD following BMT. Hypotheses: Lymphotoxin alpha, a member of the TNF superfamily of signalling molecules, contributes to GVHD pathology TNF is well established as one of the key pathogenic cytokines in GVHD, and thus it was hypothesised that the related cytokine, lymphotoxin alpha, which signals through the same two receptors, would also contribute to GVHD. Using mouse models of GVHD, I was able to confirm that lymphotoxin alpha is indeed a critically important molecule in GVHD pathology, inducing apoptosis within recipient gastrointestinal tract and skin. This is a clinically important finding, as TNF blockade is now part of standard GVHD therapy, but some agents (e.g. Infliximab) block only TNF, whereas others inhibit both TNF and soluble lymphotoxin (e.g. Etanercept). Recipient plasmacytoid DC do not play a role in the initiation of GVHD Studies defining the role of antigen presenting cell (APC) subsets in both host and donor-mediated antigen presentation have been extremely limited to date. Previous studies within this laboratory sought to clarify the role of plasmacytoid dendritic cells (pDC) and established that host pDC were exquisitely sensitive to radiation and largely absent by the time donor grafts were transferred and that donor pDC fail to mature during GVHD, due to developmental arrest at the “pre-DC” stage. Based on this knowledge, I sought to further examine the role of recipient pDC in the initiation of T cell responses, and confirmed that they were highly unlikely to contribute to the priming of alloreactive T cells after BMT. Subsets of donor APC play differential roles in alloantigen presentation To assess the relative contribution of different APC subsets to alloantigen presentation, transplants were performed using the C57Bl/6 → BALB/c model of allogeneic BMT. Using this system, the TEa transgenic T cell could be used to measure alloantigen presentation, as the TEa has a T cell receptor (TCR) specific for a host-derived peptide presented in the context of donor MHC II molecule. Following transplantation, APC subsets were systematically removed using conditional depletion methods (i.e. CD11c.DTR for cDC, MAFIA donors for macrophages and cDC) and monoclonal antibodies (i.e. 120G8 mAb specific for pDC), and TEa T cells were adoptively transferred in order to quantify alloantigen presentation in the absence of each APC subset. As a result of this study, donor conventional dendritic cells (cDC) were confirmed as the critical donor APC for presenting alloantigen after BMT. GVHD-associated immune suppression occurs due to post-transplant APC dysfunction The final component of this thesis has involved the use of the experimental methods established during my PhD candidature to examine the function of the reconstituting donor immune system following BMT. This work demonstrates that donor cDC function is markedly impaired in the context of GVHD due to a defect MHC-II presentation, arising due to the absence of the CD4+ cDC subset in combination with decreased function of the double-negative (DN) cDC subset. Identifying this defect in cDC development and function during GVHD has important implications for the design of therapies to improve post-transplant immunity, and investigation of interventions to reverse this defect form the basis for ongoing work. The experimental work contained within this thesis addresses several issues; it identifies conventional dendritic cells as the key population for antigen presentation after allogeneic BMT, it confirms that the presence of GVHD after transplant induces deficits in cDC capacity to present exogenously captured antigen via the MHC II pathway, and it provides evidence that lymphotoxin is an important and previously unrecognised pathogenic cytokine in GVHD. These aspects of transplant immunology were previously unreported, and form platforms for new therapeutic interventions to modulate transplant outcome.
Keyword Bone marrow transplant (BMT)
graft-versus host disease
Graft-versus-leukaemia effects
Antigen Presentation
antigen presenting cell
dendritic cell
lymphotoxin alpha
Additional Notes Please print the following pages in colour: 35, 52, 94, 99-100, 135, 148 Please print the following pages in landscape: 87, 92-96, 99-100, 123, 141, 144-145.

 
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