Lactoferrin Modulation of Granuloma Pathology

Pharmareview Corporation, Houston TX

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT 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 human lactoferrins for use as an immune modulator to ameliorate granuloma pathology. Our aims are to determine lactoferrin's ability to limit destructive pathology, and to evaluate its immune modulatory effects an infectious challenge model of granulomatous response. To accomplish our goal, mice will be challenged with Mycobacterium tuberculosis treated with novel recombinant (CHO-derived) human lactoferrin by oral (gavage) administration. Models are set to look at both prophylactic and therapeutic treatment. Lung tissue will be evaluated 28 days post challenge for changes in histology, immunopathology and inflammatory mediators. Spleen and liver will be monitored for organism dissemination. Change in lung pathology will be evaluated to assess lactoferrin's ability to alter delivery of antimycobacterial therapeutics to regions of infectivity within tissue. The proposal also includes production and safety/toxicity studies to validate the clinical utility of rhLF as a therapeutic, expressed in stable CHO (DG44) cells under GMP protocols. Our objectives include scale-up production of GMP quality of rhLF using a stable CHO cell line and assessment of safety using pre-IND, single and repeat day dose toxicology protocols in rats. Overall, these studies will (1) evaluate 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 factors. This approach represents a novel therapeutic strategy for potential treatment of tuberculosis disease.