Fellowship: Role of Dendritic Cells in Host Defense Against Pneumycystis Carinii in Neonates

Neonates and young infants are highly susceptible to respiratory infections due to some incompletely understood defects in the immune system. Opportunistic infections like Pneumocystis carinii (PC) often cause significant morbidity and mortality especially in neonates and infants immunocompromised by AIDS, cancer chemotherapy or organ transplantation. Studies from this laboratory reported a delayed clearance of PC organisms from the lungs of neonatal mice with an associated delayed onset of inflammatory response suggesting an immature lung environment rather than an intrinsic immaturity in T cells. Inefficient dendritic cell (DC) function in the neonatal respiratory tract may be involved in the defective neonatal host-responses to respiratory pathogens including PC. The goal of this proposal is to examine the ability of neonatal DC to' efficiently present antigen and thereby induce an effective T cell response to PC. The hypothesis to be tested is that migration of neonatal DC to the draining lymph nodes is inefficient and results in delayed proliferation and activation of the effector T cells and delayed resolution of PC pneumonia (PCP). The specific aims of this proposal are 1) to determine whether antigen uptake and migratory efficiency of DC is different in the neonatal as compared to adult lung environment, 2) to determine whether neonatal DCs upregulate costimulatory molecules and efficiently produce cytokines in response to PC. The,se experiments will lead to a much better understanding of ,neonatal host-responses to lung infections, in particular the role of DC, which may lead to new strategies to protect newborn infants from often fatal respiratory infections.