Immunomodulatory role of PU DNA-stimulated dendritic cells Mycobacterium tuberculosis antigens in experimental TB

• Grant number: 06/04677-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): December 01, 2006
• Effective date (End): July 31, 2008
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Vânia Luiza Deperon Bonato
• Grantee: Rubens Rodrigues dos Santos Junior
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

In developing countries, tuberculosis (TB) remains one of the three most common fatal infectious diseases, along with acquired immune deficiency syndrome and malaria. The BCG vaccine protects against disseminated disease in childhood, but does not protect against adult pulmonary TB. A new vaccine against TB would need to induce protection superior to that elicited by the BCG vaccine and to permit administration to healthy individuals, infected individuals and perhaps even individuals presenting the active form of the disease. Despite the prophylactic and therapeutic effects against experimental pulmonary TB induced by the DNA-hsp65 vaccine described previously, our group pointed its optimization as an important aspect to be considered. The amount of doses, route and easiness of administration also are important points to consider in the design of new vaccines, prophylactic or therapeutic. These vaccines must be able to inducing T cell responses in animals and in humans. In this context, dendritic cells also are considered an important tool for the improvement of the immune response. Dendritic cells (DC) are highly specialized immune cells which are unique in their ability to initiate and maintain primary immune responses. Their crucial functions comprise antigen presentation, stimulation and regulation of antigen specific T lymphocyte responses. The pivotal role of DC in priming immune responses has prompted hopes that DC, upon specific loading with Ag, may serve as natural adjuvants. Indeed, several studies have documented the therapeutic potential of DC-based immune interventions in a variety of murine tumor models and, more recently, in clinical trials. However, only a few studies so far have explored the in vivo efficacy of DC-mediated vaccination in infectious disease settings. Recently, some studies have showed that DC pulsed in vitro with mycobacterial antigens can efficiently stimulate specific T cells in vivo when injected into mice and also can afford substantial protection against Mycobacterium tuberculosis infection. However, the effect of therapeutic vaccine based on DC pulsed with antigen has not been evaluated in experimental TB. In this sense, our aim is to evaluate the efficacy of the immune therapy with DC pulsed with DNA-hsp65 and/or mycobacterial proteins as well as the pattern of immune response in mice experimentally infected with M. tuberculosis. (AU)