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Title: Monoclonal antibody therapy of multiple sclerosis
Author: Coles, A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1998
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T cells mediate the inflammatory activity of multiple sclerosis, which is directed against an unknown autoantigen. A non-antigen specific treatment strategy was tested, drawing on the experimental demonstration of long term allograft acceptance following short term therapy with monoclonal antibodies against T cells. The treatment of 27 patients with multiple sclerosis using a single pulse of humanised anti-lymphocyte (CD52) antibody, Campath-1H, was investigated. With the first dose of monoclonal antibody, patients experienced a rehearsal of previous relapses that fully resolved and was associated with a transient rise in serum TNF-α and IFN-γ. This suggested that inflammatory mediators may impede axonal conduction at previously demyelinated sites. After five consecutive daily doses of Campath-1H, the circulating T lymphocyte count was suppressed for at least 18 months, without any serious infective complications. The in vitro mitogen induced proliferation, and IFN-γ secretion, of patients' peripheral blood mononuclear cells was reduced after treatment and there was also a signficant rise in the peripheral B cell count above pre-treatment levels. This deviation of immune responses away from the Th1 phenotype would, under the hypothesis that multiple sclerosis is a "Th1 disease", be expected to abrogate cerebal inflammation. Unexpectedly, one third of patients developed Graves' disease, an adverse effect not induced by any other therapies nor by Campath-1H treatment of other diseases. By analogy with experimental models of autoimmunity following prolonged lymphocyte depletion, Campath-1H may have selectively depleted T cell clones which suppress autoreactive T cells, although why Graves' disease specifically was induced remains unexplained. Radiological markers of cerebral inflammation were suppressed for at least 18 months in all patients, who experienced no new relapses. However half the patients continued to accumulate disability from deficits acquired prior to monoclonal antibody treatment. In these patients there was both a higher inflammatory load at baseline and progressive cerebral atrophy, which may represent axonal degeneration. It is concluded that inflammation is a necessary prerequisite for new lesion formation and that the secondary progressive phase of multiple sclerosis is initiated by demyelination but proceeds by non-inflammatory mechanisms.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available