Lactoferrin Modulation of Granuloma Pathology

ABSTRACT Host immunity plays a major role in development of Tuberculosis diseaseTuberculosis infected individuals respond by formation of granulomaswhich contain bacilliHoweverorganisms within granulomas are protected from the full scope of immune mediated defensesWe hypothesize that modulation of destructive immune mediated pathologywhile preserving essential immune responseswill allow more effective immune controlThe goal of these studies is therefore to assess bioactivity of novel recombinant human lactoferrins for use as an immune modulator to ameliorate granuloma pathologyOur aims are to determine lactoferrin s ability to limit destructive pathologyand to evaluate its immune modulatory effects an infectious challenge model of granulomatous responseTo accomplish our goalmice will be challenged with Mycobacterium tuberculosis treated with novel recombinantCHO derivedhuman lactoferrin by oralgavageadministrationModels are set to look at both prophylactic and therapeutic treatmentLung tissue will be evaluateddays post challenge for changes in histologyimmunopathology and inflammatory mediatorsSpleen and liver will be monitored for organism disseminationChange in lung pathology will be evaluated to assess lactoferrin s ability to alter delivery of antimycobacterial therapeutics to regions of infectivity within tissueThe proposal also includes production and safety toxicity studies to validate the clinical utility of rhLF as a therapeuticexpressed in stable CHODGcells under GMP protocolsOur objectives include scale up production of GMP quality of rhLF using a stable CHO cell line and assessment of safety using pre INDsingle and repeat day dose toxicology protocols in ratsOverallthese studies willevaluate bioactivity of oral delivered novel recombinant mouse lactoferrin for use as a preclinical research tool in a mouse infectious challenge system to alter granuloma pathology to tuberculosis related factorsThis approach represents a novel therapeutic strategy for potential treatment of tuberculosis disease