Our laboratory is interested in understanding the basic mechanisms of the innate immune response and hoping to apply these basic concepts to the treatment of human diseases. We are particularly interested in tuberculosis and lung cancer.
Epidemiological and laboratory studies suggest that vitamin A is important in host defense against Mycobacterium tuberculosis infection, the etiological agent of tuberculosis. Individuals with deficient serum levels of vitamin A, which circulates in its inactive form (retinol), are more susceptible to tuberculosis. In laboratory experiments, stimulation of M. tuberculosis-infected human macrophages with the bioactive form of vitamin A (all-trans retinoic acid, ATRA) resulted in an antimicrobial response against the pathogen. Therefore, it is likely that vitamin A plays an important role in host defense against M. tuberculosis, and we are attempting to elucidate several key aspects of this pathway including: i) the vitamin A induced molecular antimicrobial mechanism, ii) how retinol is utilized by immune cells, and iii) how the vitamin A pathway interacts with the innate immune response as a whole. Using the information gained from these studies, we hope to develop novel immunotherapeutics for the treatment of tuberculosis.
Inoperable cancers carry a significantly worse prognosis as compared to cancers that can be treated surgically. For late stage inoperable lung cancers (i.e. stage 3B and stage 4), treatment is usually chemotherapy or radiation therapy, both of which have serious side effects. The effectiveness of these treatments are generally limited, as evidenced by the fact that lung cancer is the leading cause of cancer related deaths in the United States, more than breast, prostate, colon, liver, melanoma and kidney cancers combined. Therefore, new therapies must be developed in order to combat this disease.
Clinical studies have shown that presence of two key innate immune cell types, the dendritic cell and macrophages, in cancers masses improves patient prognosis; however, there is a well-documented ability of cancers to exclude and inhibit the function of these cells. We propose to develop a novel personalized immunotherapeutic strategy for the treatment of lung cancers which targets dendritic cells and macrophages to the cancer through genetic tailoring. Since interactions between chemokines and their receptors are largely responsible for the migration and ultimate destination of immune cells, we propose to take advantage of the chemokines endogenously expressed by lung cancer. Using these tailored dendritic cells and macrophages we hope to i) elicit a cancer specific immune response, ii) delivery biotherapeutic molecules such as anticancer peptides, and iii) circumvent cancer induced immune suppression.
Key Words: Vitamin D, Vitamin A, tuberculosis, innate immune response, lung cancer, iPS