The project is a patient-based cellular and molecular-genetic analysis of the cellular immune response to tuberculosis infection in the human host.
The specific aims of this project are: (1) To determine whether there is a difference in immune activation among PPD+ individuals (patients and controls), following varying types of exposure to mycobacterial antigens, in specific tissue compartments (skin, blood and pleural space); (2) to determine the efficacy and mechanism of action of recombinant human IL-2 administered to patients with multi-drug resistant (MDR) tuberculosis; and (3) to understand which molecular and cellular events of immune activation are involved in the activation of antimicrobial activity in vitro. Immunologic parameters will be studied in the pleural space (a site of primary TB infection), the blood (the most easily accessible systemic compartment) and the skin (the site of DTH manifestation and the most likely site for vaccine delivery). Specifically, the investigators will assess changes in (a) delayed type hypersensitivity skin test response to PPD (antigen- dependent) and IL-2 (antigen independent); (b) cytokine gene activation in the blood, the pleural space and the skin; and (c) phenotype and in vitro function of leukocytes isolated from blood and pleural effusions. In a blinded, placebo-controlled study, the investigators will determine whether adjunctive therapy with rhuIL- 2 is efficacious in improving acid fast bacillary clearance in sputum, clinical symptoms, and radiologic manifestations in patients with MDR-TB who have failed to respond to conventional therapy; they will also determine how adjunctive IL-2 therapy impacts on immunologic parameters. By using differential display and quantitative RT-PCR, electron microscopy, immunohistology and histopathology of biopsied DTH response sites, they will study immunologic and molecular genetic changes following exposure to mycobacterial antigens, treatment of the active disease, and adjunctive IL-2 therapy. They will investigate how changes in specific gene expression contribute to antimicrobial activities, using in vitro leukocyte activation and infection models. For this study, a team of collaborators has been assembled from the Rockefeller University, University of Cape Town, Groote Schuur Hospital, and the National Institute for Medial Research (Mill Hill, London). The applicant believes that the studies will provide essential information for identifying correlates of protective anti-tuberculous immunity, important for the evaluation of new therapeutic modalities, new anti-tuberculous vaccines, and new skin test reagents on patients with tuberculosis.
Showing the most recent 10 out of 11 publications
