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Mechanisms of action of interferon-alpha in B-cell chronic lymphocytic leukaemia

Jewell, Andrew Paul; (1993) Mechanisms of action of interferon-alpha in B-cell chronic lymphocytic leukaemia. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Interferon-alpha is able to produce partial responses in patients with early stage B cell chronic lymphocytic leukaemia (CLL), but the responses are highly variable, both in extent and duration. This thesis explores the possible cellular bases for these clinical responses and their heterogeneity, and addresses the adhesive properties of CLL cells, in relation their homing behaviour, as well as the cytokine regulation of CLL cell survival and apoptosis, and the role of effector cells, using both in vitro and in vivo studies. In a current clinical trial conducted in patients with early stage CLL, interferon-alpha produced partial responses, in terms of a significant reduction in lymphocyte counts, and the development of anti-interferon antibodies correlated with loss of clinical response. There was little evidence for T cell activation in patients receiving interferon, but there were significant rises in serum levels of macrophage colony-stimulating factor (M-CSF) and neopterin, suggesting that mononuclear cell activation may be involved in the generation of haematological responses to interferon-alpha. Normal lymphocytes undergo well regulated patterns of recirculation in vivo, and abnormal patterns may be involved in the pathophysiology of CLL. CLL cells have abnormal expression of adhesion and homing molecules, and interferon-alpha was able to induce surface expression of the lymphocyte homing receptor, L-selectin. The binding properties of CLL cells to cultured human high endothelium, and umbilical vein-derived endothelium, in the context of cytokine stimulation, were examined. CLL cells express the bcl-2 oncoprotein, but do not possess the t(14;18) translocation. In vitro, CLL cells demonstrate high levels of spontaneous apoptosis, and interferon-alpha was able to increase expression of the bcl-2 protein, both in vitro and in vivo, and to protect these cells against both spontaneous and induced apoptosis. Several cytokines have been implicated in the autocrine control of growth and differentiation of CLL cells. In this study, cytokines such as IL-6 and TNF, as well as soluble CD23, were detected in the peripheral blood of patients with CLL, however, the question of their potential role as autocrine growth factors remains unresolved. The ability of several cytokines, including interferons-alpha and gamma, and the interleukins to protect CLL cells against apoptosis may be relevant to this question.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Mechanisms of action of interferon-alpha in B-cell chronic lymphocytic leukaemia
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Chronic lymphocytic leukaemia
URI: https://discovery.ucl.ac.uk/id/eprint/10101416
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