The ultimate goal of this research program is to elucidate the mechanisms by which vaccination protects against pulmonary tuberculosis. To accomplish this goal a guinea pig model has been developed in which chronic, moderate protein deficiency is used to mimic the non-responder pole of the clinical tuberculosis spectrum. Identification of the mechanisms by which protein malnutrition impairs vaccine efficacy will reveal the key aspects of the immune response which contribute to protection. Three powerful tools developed during the previous funding period will be used in the proposed studies. Those tools are (a) the ability to induce a pleural effusion which serves as an accessible source of recirculating cells which are responding to inflammatory stimuli; (b) the application of monoclonal antibodies against guinea pig CD4+ and CD8+ T cell subsets in flow cytofluorometric and immunohistochemical analyses; and (c) the development of an adoptive transfer protocol between syngeneic Strain 2 guinea pigs. These procedures will be applied in experiments which are designed to address the following specific aims: (1) To utilize Mycobacterium bovis BCG and attenuated Mycobacterium tuberculosis H37Ra in order to establish the importance of homology between the """"""""immunizing"""""""" and """"""""challenge"""""""" organisms in the adoptive transfer of resistance to pulmonary challenge with M. tuberculosis H37Rv; (2) To determine the impact of pooling or sequestration of protective cells on the expression of resistance to pulmonary tuberculosis in protein deficient guinea pigs; (3) To elucidate the influence of protein deficiency on CD4/CD8 ratios, clonal expansion, and accessory cell function as mechanisms to explain failure of LP cells to transfer effective resistance to normal recipients; (4) To quantify the anti-mycobacterial effector mechanisms (macrophage activation, control of intracellular mycobacteria) expressed in protein-deprived guinea pigs; and (5) To delineate the effect of protein deficiency on granuloma formation and control of the bacillemic phase of pulmonary tuberculosis.
Showing the most recent 10 out of 55 publications
