Depletion of Dendritic Cells to Prevent Acute Graft Versus Host Disease.

John Wilson (2008). Depletion of Dendritic Cells to Prevent Acute Graft Versus Host Disease. PhD Thesis, Southern Clinical Division, The University of Queensland.

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Author John Wilson
Thesis Title Depletion of Dendritic Cells to Prevent Acute Graft Versus Host Disease.
School, Centre or Institute Southern Clinical Division
Institution The University of Queensland
Publication date 2008
Thesis type PhD Thesis
Supervisor Dr. David Munster
Dr. Alison Rice
Prof. Derek Hart
Total pages 193
Total colour pages 31
Total black and white pages 162
Subjects 11 Medical and Health Sciences
Abstract/Summary Acute graft versus host disease (aGVHD) affects more than 40% of patients undergoing haematopoietic stem cell transplantation. aGVHD occurs after transplantation of donor haematopoietic cells into hosts incapable of rejecting the donor cells, when donor T cells attack host tissue. Despite extensive efforts, aGVHD remains problematic to prevent and difficult to control. Current therapies to prevent aGVHD induce profound immunosuppression, leaving patients at increased risk of infection and leukaemic relapse. Dendritic cells (DC) are professional antigen presenting cells of haematopoietic origin and are the primary stimulators of the immune system, uniquely being able to activate naïve T cells. A growing body of evidence suggests that DC are responsible for the stimulation of the donor T cells which cause aGVHD. I have used a model of aGVHD which utilizes conditioned severe combined immunodeficient mice transplanted with human peripheral blood mononuclear cells (PBMC). In this model human CD4+ T cells appear to be responsible for an aGVHD-like syndrome which results in death 15-30 days post transplant. I have shown, using in vitro depletion of individual populations, that other subpopulations of human PBMC did not affect the survival of the mice. I have also demonstrated that human DC are required for the induction of aGVHD in the majority of mice. This novel finding validated the use of this model to test the primary hypothesis; that antibody mediated depletion of DC would prevent aGVHD. The murine IgM monoclonal antibody (Mab), CMRF-44 Mab, is specific for an unknown molecule expressed on the surface of activated human DC. Previous work had shown that when mixed lymphocyte reaction stimulator cells were depleted of CMRF-44+ cells, there was a significant reduction in the proliferation of responder cells. Here I tested the efficacy of CMRF-44 as a therapy for the prevention of aGVHD in the model. CMRF-44 Mab did not improve survival of mice treated with human PBMC, despite recent data showing that CMRF-44 expression on DC was predictive of aGVHD in patients. In vitro depletion of CMRF-44+ cells from human PBMC prior to transplantation also did not reduce incidence of aGVHD. An alternate target for the depletion of human DC was CD83 which is also expressed on the surface of activated human DC. I generated a rabbit polyclonal antibody using a human CD83 fusion protein, which was then affinity purified in a multi-step process which yielded only antibody specific for human CD83. Treatment with this antibody greatly improved survival of transplanted mice. Further experiments showed that anti-CD83 treatment did not abrogate human leucocytes including CD8+ memory T cells suggesting that a therapy using an anti-CD83 antibody has the potential to prevent aGVHD without the immunosuppression associated with current anti-aGVHD therapies. The work described here has validated the use of a human mouse chimeric model as an in vivo assay of human DC function and shown that targeting CD83 has the potential to reduce the incidence of clinical aGVHD whilst preserving donor memory T cells.
Keyword Graft versus host disease
Haematopoietic stem cell transplantation
Dendritic cell
Peripheral blood mononuclear cells
Additional Notes Color pages (PDF page numbers) 1, 35, 53, 64, 79, 87, 89, 91, 92, 95, 98, 100, 101, 107, 117, 118, 120, 122, 124, 126, 127, 136, 142, 144, 146, 154, 155, 157, 173, 174, 175

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Created: Mon, 22 Feb 2010, 14:17:14 EST by Mr John Wilson on behalf of Library - Information Access Service