Immune regulation in multiple myeloma : the host-tumour conflict
The data presented in this thesis demonstrates that the malignant plasma cells of multiple myeloma are capable of suppressing the activation of T lymphocytes. The myeloma cells prevent activation of T cells from healthy donors by allo-antigen, mitogen and IL-2, mediated by the production of soluble, immuno-suppressive factor. This factor was responsible for inducing cell cycle arrest and failure of the T cells to progress into the autocrine IL-2 autocrine pathway, which is of critical importance in the activation of T cells. To further investigate this interaction an in vitro model system was developed to examine the key stages of T cell activation and homeostasis. Myeloma cells constitutively expressed high levels of TGF-1 mRNA transcripts as detected by RT-PCR which were translated into latent protein and secreted as detected by immunohistochemistry and ELSIA, respectively. The reversal of the immuno-suppression induced by the myeloma cells using the specific TGF-1 antagonist, Latency Associated Peptide, confirmed that TGF-1 is a major factor in myeloma-associated suppression of T lymphocyte activation. It was demonstrated that the myeloma cells prevent the T cells, upon activation, from up-regulating the surface expression of the -chain of the IL-2R thus preventing the formation of the high-affinity receptor. The reduced expression of IL-2R resulted from altered transcription of the -chain gene in response to re-stimulation of primary T cells with IL-2. When signalling events in primary T cells responding to re-stimulation with Il-2 was examined, myeloma cells inhibited the phosphorylation of both STAT3 and STAT5. However, using a novel IL-2-dependnet T cell line (IDBL), which does not require the expression of the high affinity IL-2R for its responses to IL-2, it was shown that these cells are insensitive to the myeloma-derived TGF-, in terms of DNA synthesis and proliferation, despite demonstrating failure of phosphorylation of STAT5. It was demonstrated that phosphorylation of STAT3 was unchanged when IDBL cells were co-cultured with myeloma cell lines.