Major Findings and Publications
In our research, we have developed a model of respiratory re-exposure to Mycobacterium tuberculosis (Mtb) based on the technique of research bronchoscopy with segmental bronchoscopic antigen challenge. This technique has been used extensively to model lung immune events in the development of asthma. For these studies, allergens that induce asthmatic attacks, such as ragweed, have been instilled into an isolated area of one lung in order to induce a localized asthmatic response. In order to study recall responses to Mtb, we have adapted this procedure by using the TB skin-test reagent purified protein derivative of Mtb (PPD) as the challenge reagent.
We have demonstrated that healthy individuals with latent tuberculosis infection (LTBI) have the ability to rapidly mobilize additional protective cells to their lungs in response to PPD challenge, whereas as control subjects without immunity to Mtb do not do so. The recruitment of immune cells follows rapid production of IFNγ-inducible chemokines ligands of CXCR3, including Mig (CXCL9) and IP-10 (CXCL10). Bronchoalveolar lavage (BAL) cell production of these chemokines in response to PPD is likewise observed only in individuals with LTBI, and is associated with a baseline 20-50 fold enrichment of Mtb-specific Th1-like CD4+ T-cells within the lungs of these subjects as compared to their own peripheral blood. Localization of Mtb-specific T-cells to the lung both at baseline and following PPD challenge appears to be largely dependent on expression of the α4β1 integrin homing molecule. Preliminary studies suggest that TB vaccination using intradermal injection of BCG is significantly less effective than respiratory exposure to Mtb at inducing the localization of Mtb-specific cells to the lung at baseline.
Future studies will be directed at determining whether suboptimal development of local immunity to Mtb within the lung following current TB vaccination can explain the inadequate ability of BCG to protect against the development of pulmonary TB. The measures of local Mtb-specific immunity that we are investigating may ultimately serve as markers for the potential efficacy of newer TB vaccination strategies.