Yentis, Steven Marc; (1994) Factors affecting the cytokine response in relation to sepsis in the intensive care unit. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The cytokines tumour necrosis factor-α (TNFα), interleukin-1β (IL-1β) and interleukin-6 (IL-6) are considered central to the pathophysiology of sepsis, which is a major cause of morbidity and mortality in the Intensive Care Unit (ICU). Gram- negative endotoxin (lipopolysaccharide) is a potent initiator of cytokine production experimentally, and may play a part in clinical sepsis. Therapies for sepsis under development include antibodies against endotoxin or specific cytokines. One consequence of antibody therapy is formation of immune complexes, which may themselves affect cytokine production. Experiments were performed which suggested modulation of the endotoxin-induced cytokine response in whole blood by presentation of endotoxin within immune complexes containing polyvalent IgG (Sandoglobulin; Sandoz Products Ltd.) or a human monoclonal IgM directed against endotoxin (HA-1A (Centoxin); Centocor). This modulation was related to complement activation, especially for IgG/endotoxin complexes. The cytokine response to IgG immune complexes without endotoxin was also complement-dependant. It was found that HA-1A was recognised by antiserum to mouse IgG, suggesting a further possible mechanism of immune complex formation in patients with heterophile antibodies. Increased IL-6 concentrations occurred in whole blood from certain ICU patients following incubation with HA-1A; this response was associated with increased mortality. Evidence was found for spontaneous production of IL-6 in vitro in blood from certain other patients. The possibility that certain patients might be "primed" for subsequent cytokine production was investigated using flow cytometry. Certain ICU patients exhibited bright staining for cytoplasmic IL-1β in peripheral blood mononuclear cells (PBMCs), but this was unrelated to clinical condition or outcome. These results suggest that immune complexes may be important in sepsis. HA-1A may induce cytokine production in vitro. Certain ICU patients appear to be "primed" for cytokine production. Use of flow cytometry to detect cytoplasmic IL-1β in PBMCs might identify "primed" ICU patients but this is of no clinical value as a predictor of clinical course.

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