UCSF

The lung is a complex mucosal organ with the responsibility of oxygenating blood for the entire body. The large surface area of the lung allows for efficient exchange of oxygen in a large blood volume but also causes vast numbers of immune cells to constantly circulate through the organ. The high tidal volumes of air inhaled results in the introduction of particles, pathogens, and allergens into this delicate system. Because of the intimate relationship between the immune cells and the lung, a delicate balance must be maintained in order to sustain life. The goal of this thesis was to develop techniques to study interactions between the environment and the immune system with a particular focus is on the mechanisms and sites of uptake and presentation of antigens in the unchallenged lung and in a mouse model of asthma.

Real-time imaging of cellular and subcellular dynamics in vascularized organs requires image resolution and image registration to be simultaneously optimized without perturbing normal physiology. This problem is particularly pronounced in the lung. Here we report video-rate, two-photon imaging of a physiologically intact preparation of the mouse lung that is stabilizing and nondisruptive.

Asthma pathogenesis is focused around conducting airways. The reasons for this focus have been unclear since it was impossible to track the sites and timing of uptake or subsequent antigen presentation to T cell effectors. Two-photon microscopy of the lung parenchyma revealed early uptake of model antigens in alveoli giving rise to the asthma-specific CD11b+ DC and antigen retention in the airway region. A hyper-reactive lung thus results from selective retention of allergen-presenting cells in airway-adjacent interaction zones, not variation in the abilities of individual cells to survey the lung.

This study elucidates the pathway of antigen from inhalation to presentation to antigen-specific T cells. These techniques can be used to study other lung diseases and can be applied to other peripheral organs. Further study and development of ways to inhibit the different steps along this pathway may lead to therapies that could be used to treat many immune related diseases.