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Lenalidomide is a second-generation immunomodulatory drug with clinical activity in mantle cell lymphoma (MCL). In vitro work shows that lenalidomide enhances NK-mediated cytotoxicity against MCL yet the significance of this in vivo remains unproven. Since NK cells are key effectors of antibody-dependent cellular cytotoxicity (ADCC), there is a clear rationale for combining lenalidomide with monoclonal antibodies. However, one concern regarding this is the potential for lenalidomide to downregulate target antigen expression on malignant B Iymphocytes. This thesis presents phase II clinical trial data (EudraCT 2007-005472- 13) confirming the safety, efficacy and immunomodulatory activity of lenalidomide in relapsed/refractory MCL. Using a novel regimen, the benefit of lenalidomide as a low-dose maintenance agent is highlighted. Peripheral T and NK cells increased in responding patients with the NK rise preceded by an initial dip suggesting tumour infiltration. Peripheral Tregs were higher in MCL patients than controls and expanded further following lenalidomide. Bioloqically relevant changes were observed in plasma IL-12p40, IL-7, IL-10, adiponectin and MMP9. A significant correlation between gender and response suggested that female patients were more sensitive to lenalidomide than males. Finally, retrospective analysis of a historical cohort confirmed that thalidomide remains a valid treatment option for MCL patients unsuitable for lenalidomide. The new-generation anti-CD20 antibodies ofatumumab and GA 101 show superiority to rituximab in several B-cell malignancies although data regarding their efficacy in MCL is scarce. Cell culture work using the MCL cell line Granta519 showed ofatumumab was superior to rituximab at inducing complement-dependent cytotoxicity whilst GA 101 was superior to both rituximab and ofatumumab at inducing direct cytotoxicity and ADCC. Combining lenalidomide with these antibodies failed to have any additive cytotoxic effect. Lenalidomide induced significant CD20 downregulation on Granta519 cells. The alternative pan-B cell markers CD19 and, to a lesser extent, CD22 were also downregulated. Thus, if lenalidomide is to be combined with monoclonal antibodies in a clinical setting, sequential administration may be more beneficial than simultaneous administration.

Hepatitis C Virus causes a persistent, chronic infection in more than 80% of the estimated 170 million infections worldwide. Persistent infection can lead to complications such as cirrhosis and hepatocellular carcinoma. Around 20% of HCV infected patients are able to spontaneously clear the infection. HCV glycoprotein E2 mediates HCV entry, and as such is the primary target for recognition by immune response. Production of broadly neutralizing antibodies to the E2 protein correlates with spontaneous clearance. However, antibody production requires efficient antigen presentation. Dendritic cells have a critical role in priming the adaptive immune response to pathogens. These cells are known as professional antigen presenting cells, that are specialise in antigen capture, uptake and presentation to cells in adaptive immunity. Priming of adaptive immunity to the HCV E2 protein is poorly understood. This study addressed this, aiming to investigate the recognition of HCV E2 envelope glycoproteins by dendritic cells. We used monocyte-derived dendritic cells MoDCs from healthy volunteers and HCV infected patients. MoD Cs are understood to provide the most potent activation of adaptive immune responses. This study analysed the binding, stimulation and eytokine production by MoDCs Following interaction with the soluble ectodomain of the E2 glycoprotein, sE2661. The activation of dendritic cells from healthy donors and HCV infected Lindividuials by the TLR4 agonist Lipopolysaccharide (LPS) and the TLR3 agonist polycytidylic acid (Poly I:C) was also analysed. It was hypothesised that the efficacy of dendritic cell recognition might contribute to the differing outcomes of HCV infection. sE2 interacted with multiple receptors on the surface of MoD Cs, including CD81 and DC-SIGN. Cell-surface expressed Mannose Receptor also bound to E2. These interactions resulted in moderate activation of MoDCs, but was associated with different profiles of cytokine release compared to cells stimulated with either LPS or Poly I:C. In both healthy donors and HCV positive patients similar expression of CD86 was observed following stimulation, either with sE2, LPS or Poly I:C. In contrast, expression of CD83 was significantly reduced in HCV infections, compared to healthy donors. MoD Cs isolated from HCV infected individuals displayed a normal cytokine production compared to healthy donors. When MoDCs were activated with combinations of sE266\ with LPS or poly I:C, di lfereuces were observed in the phenotype and production of cytokines between MoDCs isolated from healthy controls and HCV infected patients. These results demonstrate that the HCV E266\ protein is recognised by some MoDCs, resulting in up-regulated expression of the DC maturation markers CD83 and 086 and altered patterns of cytokine secretion, compared to un-stimulated cells, . This activation is not similar to that achieved with LPS or poly I:C. HCV sE2661 does not possess the capacity to induce either Th 1- or Th2-type immune responses in MoD Cs from both healthy and HCV infected patients. However, this protein induced production of TNF-a from MoDCs isolated from some healthy donors, but not from MofX's isolated from Hev -infected patients. In addition, sE2661 was found to influence MoDes function when combined with TLR ligands. It is concluded that MoDes from some HeV infected patients possess different in phenotypes to healthy controls. This may play a role in the inability to control HeV infection.

A fundamental process in the immune response to infection is the activation of T cells following contact with antigen presenting cells. This activation occurs after T cell receptors on the surface of T cells bind to immunogenic peptides expressed on the surface of antigen presenting cells. The binding of T cell receptors to ligands not only leads to the activation of T cells, it is also key to T cell selection in the thymus and the maintenance of a diverse T cell receptor repertoire. T cell receptor bindings are converted into a signal which activates a T cell but there is no universal theory which governs this process. There is experimental evidence to suggest that receptor-ligand bindings must be sufficiently long to elicit a T cell response. and that counting devices in the T cell work to allow signal accumulation, decoding and translation into biological responses. In view of these results, this thesis uses mathematical models to explore the timescales associated with T cell responses. A stochastic criterion that T cell responses occur after N receptor-ligand complexes have been bound for at least a dwell time, T, each, is used. The first model of receptor-ligand binding, in conjunction with the stochastic criterion, supports the affinity threshold hypothesis for thymic selection and agrees with the experimentally established ligand hierarchy for thymic negative selection. The initial model of ligand-receptor binding is then extended to include feedback responses, bivalent receptor binding and ligand diffusion through the immunological synapse. By including these mechanisms, the models agree with an array of experimental hypotheses which include: T cells exhibit a digital response to ligand. bivalent T cell receptor engagement stabilises receptor-ligand bindings and one ligand is sufficient to elicit a T cell response.

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