Therapeutic Effects of Intravenous Immunoglobulin, Platelet Transfusion and B Cell Depletion on Murine Immune Thrombocytopenia (ITP)
Year: 2016
Type: dissertation
Abstract: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated thrombocytopenia and increased tendency of bleeding. The pathogenesis of ITP includes both decreased platelet production by megakaryocytes in the bone marrow and increased peripheral platelet destruction in the spleen due to antibody- and T cell-mediated immune responses against self platelet antigens. To better understand the disease and its therapies, I carried out three projects focusing on antibody-mediated ITP, T cell-mediated ITP and the relationship between the two immune pathways. In the first project, I examined the number and morphology of bone marrow megakaryocytes after induction of acute thrombocytopenia by anti-platelet antibodies with different specificities and isotypes. Most of the antibodies did not appear to alter megakaryocyte morphology or maturation within 24 hours. Moreover, although IVIg therapy successfully rescued the thrombocytopenia, it did not exhibit any significant effect on the megakaryocytes. Second, using an active ITP mouse model, I investigated the effect of allogeneic platelet transfusion therapy on T cell-mediated ITP. I found an immunosuppressive effect of the allogeneic transfusions on the T cell-mediated ITP associated with a decrease in the cytotoxic activity of CD8+ T cells in vitro and normalized megakaryocyte number/morphology in the bone marrow. Third, to investigate the relationship between B and T cells in ITP, I depleted B cells in vivo and examined the changes in T cell-mediated ITP. CD8+ T cell-mediated ITP was found ameliorated after B cell depletion therapy and was associated with a decreased proliferation of CD8+ T cells that could be rescued with interleukin (IL)-2 in vitro. This study provided a novel explanation for the therapeutic effect of B cell depletion in ITP and suggests a synergistic role between B cells and T cells in initiating the disease. In summary, this thesis revealed a lack of effect of anti-platelet antibodies on megakaryocytes suggesting that T cells may be involved in mediating bone marrow effects in ITP. Related to the T cells, it further elucidated the therapeutic effects of platelet transfusions and B cell depletion therapy on T cell-mediated ITP. These results may be of importance in decisions regarding the management of ITP.
Source: TSpace (University of Toronto)
Author: Li Guo
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Ontario Trillium Foundation
OpenAlex ID: W2561027257