2 research outputs found
ZAP-70 Phosphorylation and other prognostic factors in adult B-chronic lymphocytic leukaemia patients
AbstractB chronic lymphocytic leukaemia (B-CLL) is a disease with an enormously heterogeneous prognosis. Due to lack of effective treatments and the heterogeneity in its course, B-CLL has remained largely incurable. In the last two decades a number of biological markers have been recognised as prognostic parameters to replace clinical staging, chief among them is ZAP-70 (a T-cell cytoplasmic tyrosine protein) albeit without a full understanding of the mechanism involved.The aim of this thesis was to identify reliable prognostic factors that could be used in the management of B-CLL patients. Seventy-six B-CLL patients were studied over 30 months using a random stratified method of sampling, whereby adult B-CLL patients were recruited at different stages of the disease. Retrospective studies enabled some patients to be studied for up to 192 months. ZAP-70 expression was demonstrated in some B-CLL cells and was examined for possible phosphorylation following B-CLL cells stimulation, implying its involvement in cell signalling. Through the use of a novel method developed during the present study, B-CLL cells were stimulated via the SDF1-α-CD184 signalling pathway resulting in ZAP-70 phosphorylation. Its expression and phosphorylation was investigated alongside other prognostic factors and also correlated with B-CLL progression. More importantly, this study demonstrated that ZAP-70 positive cells are more responsive to signals derived from their surrounding environment, such as SDF-1α.In conclusion ZAP-70, CD38, and CD23 expressions together with IgVH gene mutational status were confirmed as indicators of poor prognosis. Response to external stimuli by some B-CLL cells, resulting in ZAP-70 phosphorylation represents the most novel aspect of this thesis and demonstrates ZAP-70 involvement in B-CLL signalling. Additionally, raised NK: B-CLL and T: B-CLL cell ratios were identified as good modifiable variable predictors of time to treatment that could be used for monitoring and therapeutic purposes. Since B-CLL is an incurable disease, the identification of prognostic factors could help in deciding the best time for intervention in B-CLL patients
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Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T‐cell responses and expression of immunosuppressive markers
ProblemInjectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En).Method of studyPeripheral blood mononuclear cells collected from women aged 18-34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4).ResultsCompared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+ T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed. DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline.ConclusionActivation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient