Dr. Ezzo's long-term goal is to establish a successful career in academic dentistry. His immediate career goal is to further his development as an independent researcher in the area of clinically-oriented periodontal research. The research environment established at Baylor College of Dentistry (BCD) by Dr. Christopher Cutler, in collaboration with Dr. Jacques Banchereau at the Baylor Institute for Immunological Research (BIIR), will enable Dr. Ezzo to pursue his career development in a unique scientific/clinical niche. Furthermore, Dr. Martha Nunn, a biostatistician with expertise in designing and analyzing clinical trials, will co-mentor Dr. Ezzo. Dr. Cutler has established a collaboration with Dr. J. Banchereau as a result of common interests including: 1) identification and characterization of different dendritic cell (DC) subsets in human tissues, 2) impact of DCs on infectious disease, and 3) ability of DCs to induce protective immunity against infection. At BCD and BIIR, greater than 80 percent of Dr. Ezzo's time will be appropriated for the development of a research career. A systematic plan including courses in clinical research has been developed in order to broaden the knowledge Dr. Ezzo received in his Dentist/Scientist Award training. Both the didactic and research phases of the career plan will allow Dr. Ezzo to expand his experience in clinical research and to achieve his career goals. Characterizing the interaction between the DC and A. actinomycetemcomitans (Aa) is a logical """"""""next step"""""""" in the process of career building for Dr. Ezzo. Dr. Ezzo's scientific background involves characterizing the T cell response to Aa and will be helpful in elucidating the importance of the DC in the immune response to this periodontal pathogen. DCs have been referred to as """"""""nature's adjuvant"""""""" due to their ability to efficiently prime naive T cells. Their work has established that the periodontium is a significant repository of DC subsets. Their role in the immune response to periodontal pathogens, like Aa, is presently unknown. Distinct DC subsets, derived from myeloid and lymphoid precursors, are capable of providing different cytokine microenvironments that promote either Th1 or Th2 T cell development. The DC subset elicited during an infection with Aa, therefore, may have a profound effect on the outcome of infection. The hypothesis is that the predominant DC subset elicited in LJP lesions is differentially susceptible to Aa and its leukotoxin (lkt). Lkt preferentially targets myeloid cell derived-DCs that bear sensitivity to its effects. These subsets are eliminated, contributing to a pronounced Th1 bias. An inflammatory response ensues resulting in the inappropriate destruction of periodontal tissues. This hypothesis will be addressed by the following aims: 1) to characterize in situ the DC subsets found in gingiva from UP patients before and after clinical treatment, 2) to isolate and characterize DCs from UP patients, and 3) to perform in vitro studies of DC phenotype and function after co-culture with lkt+lkt-Aa.
