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Oral Biology Program
B.D.S. 2008, Manipal University
Thesis Advisor: Scott Kachlany, Ph.D.
Department of Oral Biology
Thursday, March 13, 2014
1:00 P.M., MSB C-600
Leukotoxin (LtxA) is a protein secreted by oral bacteria Aggregatibacter actinomycetemcomitans that targets white blood cells by binding to its receptor Lymphocyte Function Antigen -1 (LFA-1). In this study, we evaluated the mechanism responsible for specificity of LtxA to diseased or activated WBCs and its clinical significance in allergic airway diseases such as asthma. Through a competitive binding assay, we found that the specificity of LtxA to activated WBCs was because of its binding to active or open conformation of LFA-1. This specificity of LtxA was applied in testing its cytotoxic potential towards activated WBCs causing damage in inflammatory lung diseases such as asthma. This migration is mediated by active LFA-1. Through ex vivo analysis, we found that PBMCs from allergic asthma patients expressed higher levels of activated LFA-1 as compared to PBMCs from matched healthy non allergic controls. We further identified two populations (CD4+CD11ahi and CD4-CD11ahi) that were significantly different between patients and controls. Further, ex vivo treatment of activated asthmatic PBMCs with LtxA, showed depletion and cell death of CD11ahi cells whereas CD11alo cells were not affected. These findings translated in vivo in a chronic allergic house dust mite (HDM) asthma mouse model characterized by Th-2 mediated allergic response. Treatment of HDM induced allergic asthmatic mice with i.p. LtxA, led to significant resolution of the disease. This resolution was quantified by disease measurables such as a reduction in total and differential BALF WBC count, reduction in lung inflammatory infiltrate, goblet cell hyperplasia and mucous production, reduction in proinflammatory cytokine levels and trend towards reduction in plasma IgE levels. These therapeutic effects were comparable or more significant than that caused by dexamethasone, which is the standard of care for asthma, and was used as a positive control treatment in our studies.
In this study, therefore, we have established a mechanism for specificity of LtxA towards activated WBCs and extended its significance in using LtxA as a potential therapy in the treatment of asthma. We have also identified the potential role of LFA-1 as a diagnostic marker in asthma.