Human cancers have developed a number of mechanisms to evade detection from the immune system or to modify it to their survival advantage. In addition to the production of directly immuno-suppressive cytokines it has also been demonstrated that regulatory cell subsets, in particular regulatory T cells. are increased in many solid tumours as well as haematological malignancies. Multiple myeloma (MM) is a mature B cell malignancy with many defects of the host immune system including humoral and cell- mediated. Prior to application of immunotherapy it is important to understand the mechanisms employed by the malignant myeloma cells to be able to influence these with more targeted therapy. I hypothesised that regulatory T cells would play an important role in the biology and progression of MM. The data presented in this thesis demonstrate that patients with MM as well as monoclonal gammopathy of uncertain significance (MGUS), the precursor of MM, have increased numbers of CD4+CD2S+FoxP3 regulatory T cells compared to healthy controls and the increase correlates with the burden of disease. The number increases further in patients treated with the immune-modulatory drug thalidomide. Regulatory T cells isolated from patient samples maintain their immune-suppressive properties. Other T cells subsets such as double negative T cells (DN T cells), Tr1 cells and T H 17 cells are also examined. In a co-culture model of human myeloma cell lines (HMCL) with peripheral blood mononuclear cells (PBMNCs) from healthy donors, it was established that the malignant plasma cells are able to expand pre-existing naturally occurring regulatory T cells (nT Reg cells) but also de novo generate tumour-induced regulatory T cells (tT Reg cells) from CD4+CD25" T cells. The generation is more effective with increasing purification of the starting population, i.e. by abolishing the influence of other cellular components such as antigen-presenting cells. The phenotypic properties of the tT Reg cells generated in this model are examined and compared to nT Reg cells. Important phenotypical differences are demonstrated. It is further established that tT Reg cells are functionally suppressive and maintain their plasticity and capability to convert into T H 17 cells, The co-culture model is further employed to examine the mechanisms behind the generation of regulatory T cells, It is established that cell-contact is the most important factor but the cytokine profile in the co-culture model is also examined. Blocking experiments reveal the partial involvement of the ICOS/ICOS~L pathway. The influence of the immuno-modulatory drug thalidomide and lenalidomide as well as a HDAC inhibitor on the generation of tTReg cells is examined. The data presented in this thesis examined the interaction of malignant myeloma cells with regulatory T cells. The data suggest that regulatory T cells in multiple myeloma could be influenced by immuno-targeted therapies such as HDAC inhibitors and directions for future research studies are suggested.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:612555 |
| Date | January 2013 |
| Creators | Feyler, Sylvia |
| Publisher | University of Leeds |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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