Lactoferrin Modulation of Granuloma Pathology



 DESCRIPTION (provided by applicant): Host immunity plays a major role in development of Tuberculosis disease. Tuberculosis infected individuals respond by formation of granulomas, which contain bacilli. However, organisms within granulomas are protected from the full scope of immune-mediated defenses. We hypothesize that modulation of destructive immune-mediated pathology, while preserving essential immune responses, will allow more effective immune control. The goal of these studies is therefore to assess bioactivity of novel recombinant mouse and human lactoferrins for use as immune modulators to ameliorate granuloma pathology. Our aims are to determine lactoferrin's ability to limit destructive pathology, and to evaluate its immune modulatory effects in the cord factor (glycolipid trehalose 6,6'-dimycolate; TDM) model of tuberculosis granulomatous response. To accomplish our goal, mice will be challenged iv with TDM, and then treated with lactoferrin via oral or iv route 24 hours later. Lung tissue will be evaluated through day 7 post TDM administration for changes in histology and inflammatory mediators. Immunopathology will be compared between mice given bovine lactoferrin, or novel recombinant (CHO-derived) mouse or human lactoferrins. These studies will (1) evaluate bioactivity of oral and intravenous delivered novel recombinant mouse lactoferrin for use as a preclinical research tool in a mouse (homologous) system to alter granuloma responses; (2) validate the mouse as a species to examine activity of heterologous recombinant human lactoferrin to alter pathology to tuberculosis-related factors; and (3) compare responses of both novel lactoferrins to bovine lactoferrin (which is not acceptable as an injectable human clinical therapeutic), to achieve confidence to move forward with Phase II testing and challenge using virulent M. tuberculosis. Overall, this approach represents a novel therapeutic strategy for potential treatment of tuberculosis disease.