Antigen presentation and dendritic cell function in malnourished children. (360G-Wellcome-067913_Z_02_A)

Malnutrition has a major impact on the health of children and is responsible for approximately 50% of all childhood deaths, mostly from infectious disease. The precise relationship between malnutrition, immune competence and infectious disease is poorly understood, yet these interrelated factors are the critical determinants of childhood morbidity and mortality. Though neglected in recent years, the association of malnutrition with defects in cell mediated immunity (CMI) is well established. Studies of CMI in malnutrition have focused on T cells, however, central to the successful generation of T cell responses is the ability of the host to present antigen to T cells. The professional antigen presenting cell in humans is the dendritic cell (DC), yet DCs have not been studied in any great detail in malnutrition, partly because the technology for their isolation and culture have only recently been established. Abnormalities of DCs have been described in early life and in association with infections such as HIV and malaria. T cell abnormalities described in severe malnutrition may be secondary to abnormalities of DCs. We propose to study DC function in a group of severely malnourished children on admission to a nutrition ward and then follow their DC function through recovery. The chosen study site in Zambia provides the ideal environment for such a study as the nutrition ward at Lusaka University Teaching Hospital admits 1,800 severely malnourished children a year and has an active research unit. During the study we will (1) characterise the patterns of DC phenotype and function in severe malnutrition, (2) describe the effects of severe malnutrition, HIV and measles on DC function, and (3) describe the impact on DC function of in vitro supplementation with micronutrients, thought to contribute to DC function. This study will provide insights into the mechanism of immune deficiency in malnutrition while also providing a rational basis for the development of novel focused micronutrient supplementation aimed at improving immune function in the severely malnourished child.