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Title: The measurement, treatment and immunopathology of leprosy type 1 reactions
Author: Walker, Stephen L.
ISNI:       0000 0004 2702 4643
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2010
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Leprosy is a chronic granulomatous condition principally affecting the skin and peripheral nerves. It is caused by infection with the obligate intracellular pathogen Mycobacterium leprae. The host immune response of an infected individual determines the disease phenotype. The borderline states of the disease are complicated by immunologically mediated Type 1 reactions in up to 30% of people. Type 1 reactions cause inflammation of the skin and peripheral nerves and can lead to permanent nerve function impairment. The treatment of Type 1 reactions is with oral corticosteroids but there are few data concerning the optimal dose and duration of corticosteroid treatment. Clinical trials have been hampered due to a lack of a valid measure of disease severity. A clinical severity scale was developed and tested in Bangladesh and Brazil. It was shown to be valid and able to discriminate between mild and moderate and moderate and severe Type 1 reactions. It was also shown to be reliable with excellent inter-observer agreement. A double blind randomized controlled clinical trial of high dose intravenous methylprednisolone and prednisolone (total dose equivalent to 6.15 g of prednisolone) was compared to placebo infusion and prednisolone (total dose 2.52 g of prednisolone). There were no significant differences in the rate of adverse effects between the two study groups. A large proportion, almost 50%, of individuals in both arms required additional prednisolone. Only 20% of individuals with nerve function impairment completely recovered although another 50% did improve. Skin biopsies were taken from participants before and at two time points during corticosteroid therapy. These biopsies were stained with monoclonal antibodies directed against toll-like receptors 1, 2, 4 and 9. Toll-like receptor 2 is highly expressed in skin lesions of Type 1 reaction but high expression of toll-like receptor 1, 2 and 4 was found in non-reactional patients with borderline lepromatous and lepromatous leprosy. The expression in the skin of the toll-like receptors 1, 2 and 4 fell during corticosteroid therapy. The gene expression of toll-like receptor 2 and 4 fell during treatment and this change in gene expression was associated with disease outcome. The human acidic ribosomal protein P0 was validated as a control gene in PCR assays in this group of patients.
Supervisor: Lockwood, D. Sponsor: American Leprosy Mission ; LEPRA ; Special Trustees of the Hospital for Tropical Diseases ; Geoffrey Dowling fellowship of the British Association of Dermatologists
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral