Immune regulatory role of therapy with dendritic cells stimulated with DNA or mycobacterial antigens in experimental tuberculosis

Abstract

Several data collected over the years showed the protective role of DNA-HSP65 vaccine in experimental tuberculosis (Lowrie et al., 1997; Bonato et al., 1998; Silva et al., 1999; Silva et al., 2004). In parallel to the prophylactic effect, we also verified that mice previously infected and treated with this vaccine were able to restrict significantly the experimental infectious process (Lowrie et al., 1999; Bonato et al., 2004; Silva et al., 2005).Approximately two million people die of tuberculosis each year, and there are eight million new cases annually (WHO, 1999). Although there are drug treatments available, the regimens are lengthy, and involve multiple drugs, and can have side effects. It is estimated that 5-10% of persons infected with M. tuberculosis present with active disease. In this sense, our results are promising since the DNA-HSP65 construct could be also used to treat infected individuals. However, it was described recently that the protective efficacy of DNA vaccines was suboptimal when evaluated in models involving non-human primates and also in phase I clinical trials (Orme, 2003; 2005). In this context, the optimization of DNA vaccines is an essential step to continue the studies regarding the use of these preparations either as a prophylactic or a therapeutic schedule. Dendritic cells are described as the most efficient professional antigen presenting cells. They promote the activation of immune responses mediated by B and T cells (Banchereau et al., 1998). Their potential as immune therapy against tumor has been largely studied (Barbuto et al., 2004, O'Neill et al., 2004, Neves et al., 2005). Dendritic cells constitute a complex system of cells according to generation, differentiation and function. The distinct populations and functions of dendritic cells that result in the activation of heterogeneous populations of T lymphocytes is one of the most investigated issues nowadays (Banchereau et al., 1998). DNA vaccines, a biological tool that could have a relevant function in the treatment of tuberculosis, if efficiently optimized, allied to the utilization of dendritic cells, could result in a strategy more efficient of stimulation of T lymphocytes. In this sense, the purpose of this project is to treat mice infected with M. tuberculosis with dendritic cells differentiated from bone marrow precursors from healthy or infected mice, stimulated in vitro with DNA and/or mycobacterial antigens. (AU)