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 lactoferrinandapos s ability to limit destructive pathology and to evaluate its immune modulatory effects in the cord factor glycolipid trehalose andapos 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 hours later Lung tissue will be evaluated through day 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 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 validate the mouse as a species to examine activity of heterologous recombinant human lactoferrin to alter pathology to tuberculosis related factors and 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 PUBLIC HEALTH RELEVANCE Host immunity plays a major role in development of Tuberculosis disease Infected hosts respond by the formation of granulomas which help to contain the bacilli However organisms within granulomas are protected from the full scope of immune mediated defenses Modulation of immune mediated destructive pathology while preserving essential immune responses will allow more effective immune control These studies will capitalize on our experience using novel recombinant mouse and human lactoferrins as immune modulators to ameliorate granulomas in a TB induced pathology model offering a novel therapeutic strategy for treatment of tuberculosis disease